2-pyrazinone derivatives for the treatment of disease or condition in which inhibition of neutrophil elastase activity is beneficial

ABSTRACT

The invention provides compounds of formula 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 3 , R 4 , R 5 , R 14 , X and W are as defined in the specification and optical isomers, racemates and tautomers thereof, and pharmaceutically acceptable salts thereof; together with processes for their preparation, pharmaceutical compositions containing them and their use in therapy. The compounds are inhibitors of human neutrophil elastase.

FIELD OF THE INVENTION

The present invention relates to 2-pyrazinone derivatives, processes fortheir preparation, pharmaceutical compositions containing them and theiruse in therapy.

BACKGROUND OF THE INVENTION

Elastases are possibly the most destructive enzymes in the body, havingthe ability to degrade virtually all connective tissue components. Theuncontrolled proteolytic degradation by elastases has been implicated ina number of pathological conditions. Human neutrophil elastase (hNE), amember of the chymotrypsin superfamily of serine proteases is a 33-KDaenzyme stored in the azurophilic granules of the neutrophils. Inneutrophils the concentration of NE exceeded 5 mM and its total cellularamount has been estimated to be up to 3 pg. Upon activation, NE israpidly released from the granules into the extracellular space withsome portion remaining bound to neutrophil plasma membrane (See Kawabatet al. 2002, Eur. J. Pharmacol. 451, 1-10). The main intracellularphysiological function of NE is degradation of foreign organic moleculesphagocytosed by neutrophils, whereas the main target for extracellularelastase is elastin (Janoff and Scherer, 1968, J. Exp. Med. 128,1137-1155). NE is unique, as compared to other proteases (for example,proteinase 3) in that it has the ability to degrade almost allextracellular matrix and key plasma proteins (See Kawabat et al., 2002,Eur. J. Pharmacol. 451, 1-10). It degrades a wide range of extracellularmatrix proteins such as elastin, Type 3 and type 4 collagens, laminin,fibronectin, cytokines, etc. (Ohbayashi, H., 2002, Expert Opin.Investig. Drugs, 11, 965-980). NE is a major common mediator of manypathological changes seen in chronic lung disease including epithelialdamage (Stockley, R. A. 1994, Am. J. Resp. Crit. Care Med. 150,109-113).

The destructive role of NE was solidified almost 40 years ago whenLaurell and Eriksson reported an association of chronic airflowobstruction and emphysema with deficiency of serum α₁-antitrypsin(Laurell and Eriksson, 1963, Scand. J. Clin. Invest. 15, 132-140).Subsequently it was determined that α₁-antitrypsin is the most importantendogenous inhibitor of human NE. The imbalance between human NE andendogenous antiprotease is believed to cause excess human NE inpulmonary tissues which is considered as a major pathogenic factor inchronic obstructive pulmonary disease (COPD). The excessive human NEshows a prominent destructive profile and actively takes part indestroying the normal pulmonary structures, followed by the irreversibleenlargement of the respiratory airspaces, as seen mainly in emphysema.There is an increase in neutrophil recruitment into the lungs which isassociated with increased lung elastase burden and emphysema inaL-proteinase inhibitor-deficient mice (Cavarra et al., 1996, Lab.Invest. 75, 273-280). Individuals with higher levels of the NE-α₁protease inhibitor complex in bronchoalveolar lavage fluid showsignificantly accelerated decline in lung functions compared to thosewith lower levels (Betsuyaku et al. 2000, Respiration, 67, 261-267).Instillation of human NE via the trachea in rats causes lunghaemorrhage, neutrophil accumulation during acute phase andemphysematous changes during chronic phase (Karaki et al., 2002, Am. J.Resp. Crit. Care Med., 166, 496-500). Studies have shown that the acutephase of pulmonary emphysema and pulmonary haemorrhage caused by NE inhamsters can be inhibited by pre-treatment with inhibitors of NE (Fujieet al., 1999, Inflamm. Res. 48, 160-167).

Neutrophil-predominant airway inflammation and mucus obstruction of theairways are major pathologic features of COPD, including cystic fibrosisand chronic bronchitis. NE impairs mucin production, leading to mucusobstruction of the airways. NE is reported to increase the expression ofmajor respiratory mucin gene, MUC5AC (Fischer, B. M & Voynow, 2002, Am.J. Respir. Cell Biol., 26, 447-452). Aerosol administration of NE toguinea pigs produces extensive epithelial damage within 20 minutes ofcontact (Suzuki et al., 1996, Am. J. Resp. Crit. Care Med., 153,1405-1411). Furthermore NE reduces the ciliary beat frequency of humanrespiratory epithelium in vitro (Smallman et al., 1984, Thorax, 39,663-667) which is consistent with the reduced mucociliary clearance thatis seen in COPD patients (Currie et al., 1984, Thorax, 42, 126-130). Theinstillation of NE into the airways leads to mucus gland hyperplasia inhamsters (Lucey et al., 1985, Am. Resp. Crit. Care Med., 132, 362-366).A role for NE is also implicated in mucus hypersecretion in asthma. Inan allergen sensitised guinea pig acute asthma model an inhibitor of NEprevented goblet cell degranulation and mucus hypersecretion (Nadel etal., 1999, Eur. Resp. J., 13, 190-196).

NE has been also shown to play a role in the pathogenesis of pulmonaryfibrosis. NE: α₁-protenase inhibitor complex is increased in serum ofpatients with pulmonary fibrosis, which correlates with the clinicalparameters in these patients (Yamanouchi et al., 1998, Eur. Resp. J. 11,120-125). In a murine model of human pulmonary fibrosis, a NE inhibitorreduced bleomycin-induced pulmonary fibrosis (Taooka et al., 1997, Am.J. Resp. Crit. Care Med., 156, 260-265). Furthermore investigators haveshown that NE deficient mice are resistant to bleomycin-inducedpulmonary fibrosis (Dunsmore et al., 2001, Chest, 120, 35S-36S). PlasmaNE level was found to be elevated in patients who progressed to ARDSimplicating the importance of NE in early ARDS disease pathogenesis.(Donnelly et al., 1995, Am. J. Res. Crit. Care Med., 151, 428-1433). Theantiproteases and NE complexed with antiprotease are increased in lungcancer area (Marchandise et al., 1989, Eur. Resp. J. 2, 623-629). Recentstudies have shown that polymorphism in the promoter region of the NEgene are associated with lung cancer development (Taniguchi et al.,2002, Clin. Cancer Res., 8, 1115-1120.

Acute lung injury caused by endotoxin in experimental animals isassociated with elevated levels of NE (Kawabata, et al., 1999, Am. J.Resp. Crit. Care, 161, 2013-2018). Acute lung inflammation caused byintratracheal injection of lipopolysaccharide in mice has been shown toelevate the NE activity in bronchoalveolar lavage fluid which issignificantly inhibited by a NE inhibitor (Fujie et al., 1999, Eur. J.Pharmacol., 374, 117-125; Yasui, et al., 1995, Eur. Resp. J., 8,1293-1299). NE also plays an important role in the neutrophil-inducedincrease of pulmonary microvascular permeability observed in a model ofacute lung injury caused by tumour necrosis factor α (TNFα) and phorbolmyristate acetate (PMA) in isolated perfused rabbit lungs (Miyazaki etal., 1998, Am. J. Respir. Crit. Care Med., 157, 89-94).

A role for NE has also been suggested in monocrotoline-induced pulmonaryvascular wall thickening and cardiac hypertrophy (Molteni et al., 1989,Biochemical Pharmacol. 38, 2411-2419). Serine elastase inhibitorreverses the monocrotaline-induced pulmonary hypertension andremodelling in rat pulmonary arteries (Cowan et al., 2000, NatureMedicine, 6, 698-702). Recent studies have shown that serine elastase,that is, NE or vascular elastase are important in cigarettesmoke-induced muscularisation of small pulmonary arteries in guinea pigs(Wright et al., 2002, Am. J. Respir. Crit. Care Med., 166, 954-960).

NE plays a key role in experimental cerebral ischemic damage (Shimakuraet al., 2000, Brain Research, 858, 55-60), ischemia-reperfusion lunginjury (Kishima et al., 1998, Ann. Thorac. Surg. 65, 913-918) andmyocardial ischemia in rat heart (Tiefenbacher et al., 1997, Eur. J.Physiol., 433, 563-570). Human NE levels in plasma are significantlyincreased above normal in inflammatory bowel diseases, for example,Crohn's disease and ulcerative colitis (Adeyemi et al., 1985, Gut, 26,1306-1311). In addition NE has also been assumed to be involved in thepathogenesis of rheumatoid arthritis (Adeyemi et al., 1986, Rheumatol.Int., 6, 57). The development of collagen induced arthritis in mice issuppressed by a NE inhibitor (Kakimoto et al., 1995, Cellular Immunol.165, 26-32).

Thus, human NE is known as one of the most destructive serine proteasesand has been implicated in a variety of inflammatory diseases. Theimportant endogenous inhibitor of human NE is α₁-antitrypsin. Theimbalance between human NE and antiprotease is believed to give rise toan excess of human NE resulting in uncontrolled tissue destruction. Theprotease/antiprotease balance may be upset by a decreased availabilityof α₁-antitrypsin either through inactivation by oxidants such ascigarette smoke, or as a result of genetic inability to producesufficient serum levels. Human NE has been implicated in the promotionor exacerbation of a number of diseases such as pulmonary emphysema,pulmonary fibrosis, adult respiratory distress syndrome (ARDS), ischemiareperfusion injury, rheumatoid arthritis and pulmonary hypertension.

DISCLOSURE OF THE INVENTION

In accordance with the present invention, there is therefore provided acompound of formula (I)

wherein

-   -   R¹ represents hydrogen or C₁-C₆ alkyl;    -   W represents a 5-membered heterocyclic ring comprising at least        one ring heteroatom selected from nitrogen, oxygen and sulphur,        wherein at least one of the ring carbon atoms may be optionally        replaced by a carbonyl group; and wherein the heterocyclic ring        is optionally substituted by at least one substituent selected        from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, OH, NO₂, C₁-C₃        alkyl substituted by one or more F atoms, C₁-C₃ alkoxy        substituted by one or more F atoms, NR¹⁰R¹¹, C≡CR¹⁵, CONR¹⁶R¹⁷,        CHO, C₂-C₄ alkanoyl, S(O)_(X)R¹⁸ and OSO₂R¹⁹;    -   R¹⁴ represents phenyl or a 6-membered heteroaromatic ring        comprising 1 to 3 ring nitrogen atoms; said ring being        optionally substituted with at least one substituent selected        from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, OH, NO₂, C₁-C₃        alkyl substituted by one or more F atoms, C₁-C₃ alkoxy        substituted by one or more F atoms, NR¹²R¹³, C≡CR³⁰, CONR³¹R³²,        CHO, C₂-C₄ alkanoyl, S(O)_(p)R³³ and OSO₂R³⁴;    -   R¹⁰, R¹¹, R¹² and R¹³ independently represent H, C₁-C₆ alkyl,        formyl or C₂-C₆ alkanoyl; or the group —NR¹⁰R¹¹ or —NR¹²R¹³        together represents a 5 to 7 membered azacyclic ring optionally        incorporating one further heteroatom selected from O, S and        NR²⁶;    -   R¹⁵ and R³⁰ independently represent H, C₁-C₃ alkyl or Si(CH₃)₃;    -   R¹⁸, R¹⁹, R³³ and R³⁴ independently represent H or C₁-C₃ alkyl;        said alkyl being optionally substituted by one or more F atoms;    -   R³ represents phenyl or a five- or six-membered heteroaromatic        ring containing 1 to 3 heteroatoms independently selected from        O, S and N; said ring being optionally substituted with at least        one substituent selected from halogen, C₁-C₆ alkyl, cyano, C₁-C₆        alkoxy, nitro, methylcarbonyl, NR³⁵R³⁶, C₁-C₃ alkyl substituted        by one or more F atoms or C₁-C₃ alkoxy substituted by one or        more F atoms;    -   R³⁵ and R³⁶ independently represent H or C₁-C₃ alkyl; said alkyl        being optionally further substituted by one or more F atoms;    -   R⁴ represents hydrogen or C₁-C₆ alkyl optionally substituted        with at least one substituent selected from fluoro, hydroxyl and        C₁-C₆ alkoxy;    -   X represents a single bond, O, NR²⁴ or a group —C₁-C₆        alkylene-Y—, wherein Y represents a single bond, oxygen atom,        NR²⁴ or S(O)_(w); and said alkylene being optionally further        substituted by OH, halogen, CN, NR³⁷R³⁸, C₁-C₃ alkoxy,        CONR³⁹R⁴⁰, CO₂R⁶⁶, SO₂R⁴¹ and SO₂NR⁴²R⁴³;    -   or R⁴ and X are joined together such that the group —NR⁴X        together represents a 5 to 7 membered azacyclic ring optionally        incorporating one further heteroatom selected from O, S and        NR⁴⁴; said ring being optionally substituted by C₁-C₆ alkyl or        NR⁴⁵R⁴⁶; said alkyl being optionally further substituted by OH;    -   either R⁵ represents a monocyclic ring system selected from

-   i) phenoxy,

-   ii) phenyl,

-   iii) a 5- or 6-membered heteroaromatic ring comprising at least one    ring heteroatom selected from nitrogen, oxygen and sulphur,

-   iv) a saturated or partially unsaturated C₃-C₆ cycloalkyl ring, or

-   v) a saturated or partially unsaturated 4- to 7-membered    heterocyclic ring comprising at least one ring heteroatom selected    from oxygen, S(O)_(r) and NR²⁰, wherein at least one of the ring    carbon atoms may be optionally replaced by a carbonyl group,    -   or R⁵ represents a bicyclic ring system in which the two rings        are independently is selected from the monocyclic ring systems        defined in ii), iii), iv) and v) above, wherein the two rings        are either fused together, bonded directly to one another or are        separated from one another by a linker group selected from        oxygen, S(O)_(t) or C₁-C₆ alkylene optionally comprising one or        more internal or terminal heteroatoms selected from oxygen,        sulphur and NR²⁷ and being optionally substituted by at least        one substituent selected from hydroxyl, oxo and C₁-C₆ alkoxy,    -   the monocyclic or bicyclic ring system being optionally        substituted by at least one substituent selected from oxygen,        CN, OH, C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, NR⁴⁷R⁴⁸, NO₂,        OSO₂R⁴⁹, CO₂R⁵⁰, C(═NH)NH₂, C(O)NR⁵¹R⁵², C(S)NR⁵³R⁵⁴,        SC(═NH)NH₂, NR⁵⁵C(═NH)NH₂, S(O)_(V)R²¹, SO₂NR⁵⁶R⁵⁷, C₁-C₃ alkoxy        substituted by one or more F atoms and C₁-C₃ alkyl substituted        by SO₂R⁵⁸ or by one or more F atoms; said C₁-C₆ alkyl being        optionally further substituted with at least one substituent        selected from cyano, hydroxyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio and        —C(O)NR²²R²³;    -   or R⁵ may also represent H;    -   R²⁰ represents hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylcarbonyl or        C₁-C₆ alkoxycarbonyl;    -   R²¹ represents hydrogen, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; said        alkyl or cycloalkyl group being optionally further substituted        by one or more substituents selected independently from OH, CN,        C₁-C₃ alkoxy and CONR⁵⁹R⁶⁰;    -   R³⁷ and R³⁸ independently represent H, C₁-C₆ alkyl, formyl or        C₂-C₆ alkanoyl;    -   R⁴⁷ and R⁴⁸ independently represent H, C₁-C₆ alkyl, formyl,        C₂-C₆ alkanoyl, S(O)_(q)R⁶¹ or SO₂NR⁶²R⁶³; said alkyl group        being optionally further substituted by halogen, CN, C₁-C₄        alkoxy or CONR⁶⁴R⁶⁵;    -   R⁴¹ and R⁶¹ independently represent H, C₁-C₆ alkyl or C₃-C₆        cycloalkyl;    -   p is 1 or 2;    -   q is 0, 1 or 2;    -   r is 0, 1 or 2;    -   t is 0, 1 or 2;    -   w is 0, 1 or 2;    -   x is 0, or 2;    -   v is 0, 1 or 2;    -   R¹⁶, R¹⁷, R²², R²³, R²⁴, R²⁶, R²⁷, R³¹, R³², R³⁹, R⁴⁰, R⁴², R⁴³,        R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴, R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸,        R⁵⁹, R⁶⁰, R⁶², R⁶³, R⁶⁴, R⁶⁵ and R⁶⁶ each independently        represent hydrogen or C₁-C₆ alkyl;        or a pharmaceutically acceptable salt thereof.

In the context of the present specification, unless otherwise stated, analkyl, alkenyl or alkynyl substituent group or an alkyl moiety in asubstituent group may be linear or branched. Similarly, an alkylenegroup may be linear or branched.

In the definition of W, the 5-membered heterocyclic ring system may havealicyclic or aromatic properties and may thus be a saturated ring systemor a partially unsaturated ring system or a fully unsaturated ringsystem.

R¹ represents hydrogen or C₁-C₆ alkyl (e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).

In one embodiment of the invention, R¹ represents a C₁-C₄ or C₁-C₂ alkylgroup, in particular a methyl group.

W represents a 5-membered heterocyclic ring comprising at least one ringheteroatom selected from nitrogen, oxygen and sulphur, wherein at leastone of the ring carbon atoms may be optionally replaced by a carbonylgroup; and wherein the heterocyclic ring is optionally substituted by atleast one substituent selected from halogen (e.g. fluorine, chlorine,bromine or iodine), C₁-C₄ alkyl (e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl or tert-butyl), C₁-C₄ alkoxy (e.g. methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy),cyano, OH, NO₂, C₁-C₃ alkyl substituted by one or more F atoms (e.g.CH₂F, CHF₂, CF₃, CH₂CH₂F, CH₂CF₃, CF₂CF₃, CH(CF₃)₂ and CH₂CH₂CF₃), C₁-C₃alkoxy substituted by one or more F atoms (e.g. OCH₂F, OCHF₂, OCF₃,OCH₂CH₂F, OCH₂CF₃, OCF₂CF₃, OCH(CF₃)₂ and OCH₂CH₂CF₃), NR¹⁰R¹¹,C≡CR¹⁵—C(O)NR¹⁶R¹⁷, CHO, C₂-C₄ alkanoyl (e.g. methylcarbonyl (acetyl),ethylcarbonyl, n-propylcarbonyl or isopropylcarbonyl), —S(O)_(X)R¹⁸, andOSO₂R¹⁹.

In one embodiment, the group R¹⁴ and the pyrazinone ring are bonded tothe 5-membered ring W in a 1,2-relationship.

In one embodiment, W represents a 5-membered heteroaromatic ring,especially an unsubstituted 5-membered heteroaromatic ring.

Examples of 5-membered heterocyclic ring systems that may be used, whichmay be saturated or partially unsaturated or fully unsaturated includeany one of pyrrolidinyl, tetrahydrofuranyl, pyrroline, imidazolidinyl,imidazolinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinonyl,imidazolidinonyl, oxazolyl, pyrazolyl, thiazolidinyl, thienyl,isoxazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl,imidazolyl, furazanyl, triazolyl and tetrazolyl.

Preferred ring systems for group W include pyrazolyl, thiazolyl,oxazolyl and imidazolyl.

In one embodiment, W represents pyrazolyl, triazolyl, thiazolyl,oxazolyl or imidazolyl.

In one embodiment, W represents pyrazolyl or triazolyl.

R¹⁴ represents phenyl or a 6-membered heteroaromatic ring comprising 1to 3 (e.g. one, two or three) ring nitrogen atoms; said ring beingoptionally substituted with at least one (e.g. one, two, three or four)substituent selected from halogen (e.g. fluorine, chlorine, bromine oriodine), C₁-C₄ alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl or tert-butyl), C₁-C₄ alkoxy (e.g. methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy or tert-butoxy), CN, OH, NO₂, C₁-C₃alkyl substituted by one or more F atoms (e.g. CH₂F, CHF₂, CF₃, CH₂CH₂F,CH₂CF₃, CF₂CF₃, CH(CF₃)₂ and CH₂CH₂CF₃), C₁-C₃ alkoxy substituted by oneor more F atoms (e.g. OCH₂F, OCHF₂, OCF₃, OCH₂CH₂F, OCH₂CF₃, OCF₂CF₃,OCH(CF₃)₂ and OCH₂CH₂CF₃), NR¹²R¹³, C≡CR³⁰, CONR³¹R³², CHO, C₂-C₄alkanoyl (e.g. methylcarbonyl (acetyl), ethylcarbonyl, n-propylcarbonylor isopropylcarbonyl), S(O)_(p)R³³ and OSO₂R³⁴.

Examples of a 6-membered heteroaromatic ring comprising 1 to 3 ringnitrogen atoms include pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyland triazinyl. A preferred ring system is pyridinyl.

In one embodiment, one substituent on the aromatic ring of group R¹⁴should be in the 4-(para) position relative to group W.

In one embodiment of the invention, R¹⁴ represents phenyl or a6-membered heteroaromatic ring comprising 1 to 3 ring nitrogen atoms;said ring being optionally substituted with at least one substituentselected from F, Cl, CN and CF₃.

In an embodiment of the invention, R¹⁴ represents phenyl or pyridinyl;said ring being optionally substituted with at least one substituentselected from F, Cl, CN and CF₃.

In an embodiment of the invention, R¹⁴ represents a phenyl or pyridinylgroup optionally substituted with one or two substituents independentlyselected from F, Cl, CN and CF₃.

In an embodiment of the invention, R¹⁴ represents phenyl or pyridinyl;said ring being 4-(para) substituted with F, Cl or CN and optionallyfurther substituted.

In an embodiment of the invention, R¹⁴ represents phenyl or pyridinyl;said ring being 4-(para) substituted with F, Cl or CN.

R³ represents phenyl or a five- or six-membered heteroaromatic ringcontaining 1 to 3 (e.g. one, two or three) heteroatoms independentlyselected from O, S and N; said ring being optionally substituted with atleast one (e.g. one, two, three or four) substituent selected fromhalogen (e.g. fluorine, chlorine, bromine or iodine), C₁-C₆ alkyl (e.g.methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl or n-hexyl), cyano, C₁-C₆ alkoxy (e.g. methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy orn-hexoxy), nitro, methylcarbonyl, NR³⁵R³⁶, C₁-C₃ alkyl substituted byone or more F atoms (e.g. CH₂F, CHF₂, CF₃, CH₂CH₂F, CH₂CF₃, CF₂CF₃,CH(CF₃)₂ and CH₂CH₂CF₃) and C₁-C₃ alkoxy substituted by one or more Fatoms (e.g. OCH₂F, OCHF₂, OCF₃, OCH₂CH₂F, OCH₂CF₃, OCF₂CF₃, OCH(CF₃)₂and OCH₂CH₂CF₃).

In one embodiment, R³ represents a phenyl or pyridinyl ring substitutedwith at least one substituent (e.g. one, two or three substituents)independently selected from halogen, cyano, nitro, methyl,trifluoromethyl and methylcarbonyl.

In one embodiment, R³ represents a phenyl group substituted with one ortwo substituents independently selected from fluorine, chlorine, cyano,nitro and trifluoromethyl.

In another embodiment, R³ represents a phenyl group substituted with oneor two substituents independently selected from fluorine, chlorine andtrifluoromethyl.

In still another embodiment, R³ represents a phenyl group substitutedwith a trifluoromethyl substituent (preferably in the meta position).

In still another embodiment, R³ represents a phenyl group substituted inthe meta position with Br, C₁, CF₃ or CN.

R⁴ represents hydrogen or C₁-C₆ alkyl (e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl)optionally substituted with at least one substituent (e.g. one or twosubstituents) independently selected from fluoro, hydroxyl and C₁-C₆alkoxy (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, n-pentoxy or n-hexoxy).

In one embodiment, R⁴ represents hydrogen or C₁-C₄ alkyl optionallysubstituted with one or two substituents independently selected fromhydroxyl and C₁-C₄ alkoxy.

In another embodiment, R⁴ represents hydrogen.

In one embodiment of the invention, X represents a single bond or agroup —C₁-C₆ alkylene-Y—, wherein Y represents a single bond, oxygenatom, NR²⁴ or S(O)_(W); said alkylene being optionally furthersubstituted by OH, halogen, CN, NR³⁷R³⁸, C₁-C₃ alkoxy, CONR³⁹R⁴⁰,CO₂R⁶⁶, SO₂R⁴¹ and SO₂NR⁴²R⁴³.

In one embodiment of the invention, X represents a single bond or agroup —C₁-C₆ alkylene-Y—, wherein Y represents a single bond, oxygenatom, NR²⁴ or S(O)_(W); said alkylene being optionally furthersubstituted by OH, halogen, CN, NR³⁷R³⁸, C₁-C₃ alkoxy, CONR³⁹R⁴⁰, SO₂R⁴¹and SO₂NR⁴²R⁴³.

In an embodiment of the invention, X represents a group —C₁-C₆alkylene-Y— and Y represents a single bond and the alkylene moiety is alinear or branched C₁-C₆ or C₁-C₄ or C₁-C₂ alkylene, optionallysubstituted by OH, halogen, CN, CO₂R⁶⁶ or C₁-C₃ alkoxy.

In an embodiment of the invention, X represents a group —C₁-C₆alkylene-Y— and Y represents a single bond and the alkylene moiety is alinear or branched C₁-C₆ or C₁-C₄ or C₁-C₂ alkylene, optionallysubstituted by OH, halogen, CN or C₁-C₃ alkoxy.

In another embodiment of the invention, X represents unsubstituted C₁-C₂alkylene, particularly methylene.

In another embodiment of the invention, X represents a single bond.

In one embodiment of the invention, R⁴ and X are joined together suchthat the group —NR⁴X together represents a 5 to 7 membered azacyclicring optionally incorporating one further heteroatom selected from O, Sand NR⁴⁴; said ring being optionally substituted by C₁-C₆ alkyl orNR⁴⁵R⁴⁶; said alkyl being optionally further substituted by OH.

Examples of a 5 to 7 membered azacyclic ring optionally incorporatingone further heteroatom selected from O, S and NR⁴⁴ include pyrrolidine,piperidine, piperazine, morpholine and perhydroazepine.

R⁵ represents a monocyclic ring system selected from

-   i) phenoxy,-   ii) phenyl,-   iii) a 5- or 6-membered heteroaromatic ring comprising at least one    ring heteroatom (e.g. one, two, three or four ring heteroatoms)    independently selected from nitrogen, oxygen and sulphur,-   iv) a saturated or partially unsaturated C₃-C₆ cycloalkyl ring, or-   v) a saturated or partially unsaturated 4- to 7-membered    heterocyclic ring comprising at least one ring heteroatom (e.g. one,    two, three or four ring heteroatoms) independently selected from    oxygen, S(O)_(r) and NR²⁰, wherein at least one of the ring carbon    atoms may be optionally replaced by a carbonyl group,    -   or R⁵ represents a bicyclic ring system in which the two rings        are independently selected from the monocyclic ring systems        defined in ii), iii), iv) and v) above, wherein the two rings        are either fused together, bonded directly to one another or are        separated from one another by a linker group selected from        oxygen, S(O)_(t) or C₁-C₆ alkylene optionally comprising one or        more (e.g. one or two) internal or terminal heteroatoms selected        from oxygen, sulphur and NR²⁷ and being optionally substituted        by at least one substituent (e.g. one or two substituents)        independently selected from hydroxyl, oxo and C₁-C₆ alkoxy (e.g.        methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,        tert-butoxy, n-pentoxy or n-hexoxy);        the monocyclic or bicyclic ring system being optionally        substituted (on a ring atom) by at least one substituent (e.g.        one, two or three substituents) independently selected from        oxygen (e.g. to form an N-oxide), CN, OH, C₁-C₆ alkyl (e.g.        methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,        tert-butyl, n-pentyl or n-hexyl), C₁-C₆ alkoxy (e.g. methoxy,        ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy,        n-pentoxy or n-hexoxy), halogen (e.g. fluorine, chlorine,        bromine or iodine), NR⁴⁷R⁴⁸, NO₂, OSO₂R⁴⁹, CO₂R⁵⁰, C(═NH)NH₂,        C(O)NR⁵¹R⁵², C(S)NR⁵³R⁵⁴, SC(═NH)NH₂, NR⁵⁵C(═NH)NH₂,        —S(O)_(V)R²¹, SO₂NR⁵⁶R⁵⁷, C₁-C₃ alkoxy substituted by one or        more F atoms (e.g. OCH₂F, OCHF₂, OCF₃, OCH₂CH₂F, OCH₂CF₃,        OCF₂CF₃, OCH(CF₃)₂ and OCH₂CH₂CF₃) and C₁-C₃ alkyl substituted        by SO₂R⁵⁸ or by one or more F atoms (e.g. CH₂SO₂R⁵⁸,        CH₂CH₂SO₂R⁵⁸, CH(SO₂R⁵⁸)CH₃, CH₂F, CHF₂, CF₃, CH₂CH₂F, CH₂CF₃,        CF₂CF₃, CH(CF₃)₂ and CH₂CH₂CF₃); said C₁-C₆ alkyl being        optionally further substituted with at least one substituent        selected from cyano, hydroxyl, C₁-C₆ alkoxy (e.g. methoxy,        ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy,        n-pentoxy or n-hexoxy), C₁-C₆ alkylthio (e.g. methylthio,        ethylthio, n-propylthio, isopropylthio, n-butylthio,        isobutylthio, tert-butylthio, n-pentylthio or n-hexylthio) and        —C(O)NR²²R²³;        or R⁵ may also represent hydrogen.

Examples of a 5- or 6-membered heteroaromatic ring include furanyl,thienyl, pyrrolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl,thiadiazolyl, pyridinyl, pyrimidinyl and pyrazinyl. Preferredheteroaromatic rings include isoxazolyl, pyridinyl, imidazolyl andtriazolyl.

Unless otherwise indicated, a “saturated or partially unsaturated C₃-C₆cycloalkyl ring” denotes a 3- to 6-membered non-aromatic cycloalkyl ringoptionally incorporating one or more double bonds, examples of whichinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyland cyclohexenyl. A preferred cycloalkyl ring is cyclopropyl.

Unless otherwise indicated, a “saturated or partially unsaturated 4- to7-membered heterocyclic ring” as specified above denotes a 4- to7-membered non-aromatic heterocyclic ring optionally incorporating oneor more double bonds and optionally incorporating a carbonyl group,examples of which include tetrahydrofuranyl, tetramethylenesulfonyl,tetrahydropyranyl, 4-oxo-4H-pyranyl (4H-pyran-4-onyl), pyrrolidinyl,3-pyrrolinyl, imidazolidinyl, 1,3-dioxolanyl (1,3-dioxacyclopentanyl),piperidinyl, piperazinyl, morpholinyl, perhydroazepinyl (hexamethyleneiminyl), pyrrolidonyl and piperidonyl. A preferred saturated orpartially unsaturated 4- to 7-membered heterocyclic ring ispyrrolidonyl.

Examples of bicyclic ring systems in which the two rings are eitherfused together, bonded directly to one another or are separated from oneanother by a linker group include biphenyl, thienylphenyl,pyrazolylphenyl, phenoxyphenyl, phenylcyclopropyl, naphthyl, indanyl,quinolyl, tetrahydroquinolyl, benzofuranyl, indolyl, isoindolyl,indolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl,benzthiazolyl, purinyl, isoquinolyl, chromanyl, indenyl, quinazolyl,quinoxalyl, chromanyl, isocromanyl, 3H-indolyl, 1H-indazolyl,quinuclidyl, tetrahydronaphthyl, dihydrobenzofuranyl,morpholine-4-ylphenyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl,1,3-benzodioxinyl and 3,4-dihydro-isochromenyl.

In an embodiment of the invention, R⁵ represents a substitutedmonocyclic ring system as defined above.

In another embodiment of the invention, R⁵ represents a substitutedbicyclic ring system as defined above.

In another embodiment of the invention, R⁵ represents H.

In a further embodiment of the invention, R⁵ represents a monocyclicring system selected from

-   i) phenoxy,-   ii) phenyl,-   iii) a 5- or 6-membered heteroaromatic ring comprising one or two    ring heteroatoms independently selected from nitrogen, oxygen and    sulphur,-   iv) a saturated or partially unsaturated C₃-C₆ cycloalkyl ring, or-   v) a saturated or partially unsaturated 4- to 7-membered    heterocyclic ring comprising one or two ring heteroatoms    independently selected from oxygen, S(O)_(r) and NR²⁰, wherein at    least one of the ring carbon atoms may be optionally replaced by a    carbonyl group;    -   or R⁵ represents a bicyclic ring system in which the two rings        are independently selected from the monocyclic ring systems        defined in ii), iii), iv) and v) above, wherein the two rings        are either fused together, bonded directly to one another or are        separated from one another by a linker group selected from        oxygen, methylene and S(O)_(t); the monocyclic or bicyclic ring        system being substituted by one or two substituents        independently selected from OH, —S(O)_(V)R²¹ and C₁-C₄ alkyl.

In a still further embodiment of the invention, R⁵ represents amonocyclic ring system selected from phenyl or a 5- or 6-memberedheteroaromatic ring comprising one or two ring heteroatoms independentlyselected from nitrogen and oxygen, the monocyclic ring system beingsubstituted by one or two substituents independently selected from OH,—S(O)_(V)R²¹ and C₁-C₄ alkyl.

In a still further embodiment of the invention, R⁵ represents phenyl orpyridinyl substituted by —S(O)_(V)R³² wherein v represents the integer2.

In a still further embodiment of the invention, R⁵ represents phenylsubstituted by one or two substituents independently selected from OH,—S(O)_(V)R²¹ and C₁-C₄ alkyl.

In a still further embodiment of the invention, R⁵ represents H.

In a still further embodiment of the invention, R⁵ represents anunsubstituted C₃-C₆ cycloalkyl ring, particularly cyclopropyl.

In one embodiment, x is 2.

In one embodiment, p is 2.

In one embodiment, R¹⁰ and R¹¹ independently represent H, C₁-C₃ alkyl orC₂-C₃ alkylcarbonyl.

In one embodiment, R¹² and R¹³ independently represent H, C₁-C₃ alkyl orC₂-C₃ alkylcarbonyl.

In a further embodiment, R²⁰ represents hydrogen, methyl, ethyl,methylcarbonyl (acetyl), ethylcarbonyl, methoxycarbonyl orethoxycarbonyl.

In one embodiment, v is 2.

R⁵ represents hydrogen, C₁-C₆ alkyl (e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or C₃-C₈cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl); said alkyl or cycloalkyl group beingoptionally further substituted by one or more substituents selectedindependently from OH, CN, C₁-C₃ alkoxy and CONR⁵⁹R⁶⁰.

In an embodiment according to the invention, R²¹ represents C₁-C₄ alkylor C₃-C₆ cycloalkyl.

In another embodiment, R²¹ represents C₁-C₃ alkyl (particularly methyl,ethyl or isopropyl) or cyclopropyl.

In another embodiment, R⁴¹ represents C₁-C₃ alkyl (particularly methyl,ethyl or isopropyl) or cyclopropyl.

In an embodiment of the invention, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R³⁰, R³³,R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R⁴⁷, R⁴⁸, R⁶¹, R²², R²³, R²⁴, R²⁶, R²⁷, R³¹,R³², R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴,R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶², R⁶³, R⁶⁴, R⁶⁵ and R⁶⁶ eachindependently represent hydrogen or C₁-C₃ alkyl, particularly methyl,ethyl, 1-propyl or 2-propyl.

In an embodiment of the invention, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R³⁰, R³³,R³⁴, R³⁵, R³⁶, R³⁷, R³⁸, R⁴⁷, R⁴⁸, R⁶¹, R²², R²³, R²⁴, R²⁶, R²⁷, R³¹,R³², R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴,R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶², R⁶³, R⁶⁴, R⁶⁵ and R⁶⁶ eachindependently represent hydrogen or methyl.

In an embodiment of the invention, R⁶⁶ represents hydrogen.

In an embodiment of the invention,

-   -   R¹ represents methyl;    -   W represents a 5-membered heteroaromatic ring, and the group R¹⁴        and the 2-pyrazinone ring are bonded to the 5-membered ring W in        a 1,2-relationship;    -   R¹⁴ represents phenyl or pyridinyl; said ring being optionally        substituted with at least one substituent selected from F, Cl,        CN and CF₃;    -   R³ represents a phenyl group substituted with one or two        substituents independently selected from fluorine, chlorine,        cyano, nitro or trifluoromethyl;    -   R⁴ represents hydrogen;    -   X represents unsubstituted C₁-C₂ alkylene, particularly        methylene; and    -   R⁵ represents phenyl substituted by one or two substituents        independently selected from OH, —S(O)_(V)R²¹ and C₁-C₄ alkyl        wherein v represents the integer 2.

In an embodiment of the invention,

-   -   R¹ represents methyl;    -   W represents a 5-membered heteroaromatic ring, and the group R¹⁴        and the 2-pyrazinone ring are bonded to the 5-membered ring W in        a 1,2-relationship;    -   R¹⁴ represents phenyl or pyridinyl; said ring being optionally        substituted with at least one substituent selected from F, Cl,        CN and CF₃;    -   R³ represents a phenyl group substituted with one or two        substituents independently selected from fluorine, chlorine,        cyano, nitro or trifluoromethyl;    -   R⁴ represents hydrogen;    -   X represents unsubstituted C₁-C₂ alkylene, particularly        methylene; and

R⁵ represents H.

In an embodiment of the invention,

-   -   R¹ represents methyl;    -   W represents a pyrazolyl or triazolyl ring, and the group R¹⁴        and the 2-pyrazinone ring are bonded to the 5-membered ring W in        a 1,2-relationship;    -   R¹⁴ represents phenyl or pyridinyl; said ring being 4-(para)        substituted with F, Cl or CN;    -   R³ represents a phenyl group substituted in the meta position        with Br, C₁, CF₃ or CN;    -   R⁴ represents hydrogen;    -   X represents a linear or branched C₁-C₄ alkylene, optionally        substituted by OH, halogen, CN, CO₂R⁶⁶ or C₁-C₃ alkoxy; and    -   R⁵ represents H.

Examples of compounds of the invention include:

-   6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylic    acid methylamide;-   6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylic    acid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide;-   6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylic    acid ethylamide;-   6-[1-(4-cyano-phenyl)-1H-1,2,3-triazol-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydro-pyrazine-2-carboxamide;-   tert-butyl    2-[[6-[2-(4-cyanophenyl)pyrazol-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazine-2-carbonyl]amino]acetate;-   6-[3-(4-chloro-phenyl)-3H-[1,2,3]triazol-4-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylic    acid methylamide;-   6-[2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylic    acid methylamide;-   6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-(2-methoxyethyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;-   6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-(2-hydroxy-1,1-dimethylethyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;-   6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;-   6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;-   6-[1-(6-cyanopyridin-3-yl)-1H-pyrazol-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;-   6-[1-(6-cyanopyridin-3-yl)-1H-pyrazol-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;-   6-[1-(5-cyanopyridin-2-yl)-1H-pyrazol-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;-   6-[1-(5-cyanopyridin-2-yl)-1H-pyrazol-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;    and-   2-[[6-[2-(4-cyanophenyl)pyrazol-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazine-2-carbonyl]amino]acetic    acid;    and pharmaceutically acceptable salts of any one thereof.

The present invention further provides a process for the preparation ofa compound of formula (I) or a pharmaceutically acceptable salt thereofas defined above which comprises,

(a) reacting a compound of formula (II)

wherein L¹ represents a leaving group (such as halogen or hydroxyl) andR¹, R³, R¹⁴ and W are as defined in formula (I),with a compound of formula

wherein X, R⁴ and R⁵ are as defined in formula (I); or(b) reacting a compound of formula (IV)

wherein Hal represents a halogen atom and X, R¹, R³, R⁴ and R⁵ are asdefined in formula (I),with a nucleophile R¹⁴—W-M wherein R¹⁴ and W are as defined in formula(I) and M represents an organo-tin or organo boronic acid group; or(c) when W represents thiazolyl or oxazolyl, reacting a compound offormula (V)

wherein X, R¹, R³, R⁴, R⁵ and R¹⁴ are as defined in formula (I),with thiourea or formamide respectively;and optionally after (a), (b) or (c) canying out one or more of thefollowing:

-   -   converting the compound obtained to a further compound of the        invention    -   forming a pharmaceutically acceptable salt of the compound.

In process (a), the reaction may conveniently be carried out in anorganic solvent such as dichloromethane or N-methylpyrrolidinone at atemperature, for example, in the range from 0° C. to the boiling pointof the solvent. If necessary or desired, a base and/or a couplingreagent such as HATU(O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate), HOAT (1-Hydroxy-7-azabenzotriazole), HOBT(1-Hydroxybenzotriazole hydrate) or DIEA (N,N-Diisopropylethylamine) maybe added.

In process (b), the reaction may conveniently be carried out in anorganic solvent such as DMF, NMP or toluene or a mixture thereof atelevated temperature (i.e. above ambient temperature, 20° C.), forexample, in the range from 50° C. to 150° C. and in the presence of asuitable transition metal catalyst such asbis(tri-t-butylphosphine)palladium. If necessary or desired, a base suchas potassium carbonate may be added.

In process (c), the reaction may conveniently be carried out by heatingtogether the two starting materials in a suitable organic solvent suchas acetonitrile at a temperature, for example, in the range from 50° C.to 150° C.

Specific processes for the preparation of compounds of Formula (I) aredisclosed within the Examples section of the present specification. Suchprocesses form an aspect of the present invention.

The necessary starting materials are either commercially available, areknown in the literature or may be prepared using known techniques.Specific processes for the preparation of certain key starting materialsare disclosed within the Examples section of the present specificationand such processes form an aspect of the present invention.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard procedures.

Certain intermediates of formulae (II), (IV) and (V) are novel. Suchnovel intermediates form another aspect of the invention.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups may need to be protected by protecting groups. Thus, thepreparation of the compounds of formula (I) may involve, at anappropriate stage, the addition and/or removal of one or more protectinggroups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 3^(rd)edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999).

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt thereof, preferably an acid additionsalt such as a hydrochloride, hydrobromide, sulphate, phosphate,acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate,succinate, oxalate, methanesulphonate orp-toluenesulphonate.

Compounds of formula (I) are capable of existing in stereoisomericforms. It will be understood that the invention encompasses the use ofall geometric and optical isomers (including atropisomers) of thecompounds of formula (I) and mixtures thereof including racemates. Theuse of tautomers and mixtures thereof also form an aspect of the presentinvention. Enantiomerically pure forms are particularly desired.

The compounds of formula (I) and their pharmaceutically acceptable saltshave activity as pharmaceuticals, in particular as modulators of serineproteases such as proteinase 3 and pancreatic elastase and, especially,human neutrophil elastase, and may therefore be beneficial in thetreatment or prophylaxis of inflammatory diseases and conditions.

The compounds of formula (I) and their pharmaceutically acceptable saltscan be used in the treatment of diseases of the respiratory tract suchas obstructive diseases of the airways including: asthma, includingbronchial, allergic, intrinsic, extrinsic, exercise-induced,drug-induced (including aspirin and NSAID-induced) and dust-inducedasthma, both intermittent and persistent and of all severities, andother causes of airway hyper-responsiveness; chronic obstructivepulmonary disease (COPD); bronchitis, including infectious andeosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis;sarcoidosis; farmer's lung and related diseases; hypersensitivitypneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis,idiopathic interstitial pneumonias, fibrosis complicatinganti-neoplastic therapy and chronic infection, including tuberculosisand aspergillosis and other fungal infections; complications of lungtransplantation; vasculitic and thrombotic disorders of the lungvasculature, and pulmonary hypertension; antitussive activity includingtreatment of chronic cough associated with inflammatory and secretoryconditions of the airways, and iatrogenic cough; acute and chronicrhinitis including rhinitis medicamentosa, and vasomotor rhinitis;perennial and seasonal allergic rhinitis including rhinitis nervosa (hayfever); nasal polyposis; acute viral infection including the commoncold, and infection due to respiratory syncytial virus, influenza,coronavirus (including SARS) and adenovirus.

The compounds of formula (I) and their pharmaceutically acceptable saltscan also be used in the treatment of diseases of bone and joints such asarthritides associated with or including osteoarthritis/osteoarthrosis,both primary and secondary to, for example, congenital hip dysplasia;cervical and lumbar spondylitis, and low back and neck pain; rheumatoidarthritis and Still's disease; seronegative spondyloarthropathiesincluding ankylosing spondylitis, psoriatic arthritis, reactivearthritis and undifferentiated spondarthropathy; septic arthritis andother infection-related arthopathies and bone disorders such astuberculosis, including Potts' disease and Poncet's syndrome; acute andchronic crystal-induced synovitis including urate gout, calciumpyrophosphate deposition disease, and calcium apatite related tendon,bursal and synovial inflammation; Behcet's disease; primary andsecondary Sjogren's syndrome; systemic sclerosis and limitedscleroderma; systemic lupus erythematosus, mixed connective tissuedisease, and undifferentiated connective tissue disease; inflammatorymyopathies including dermatomyositits and polymyositis; polymalgiarheumatica; juvenile arthritis including idiopathic inflammatoryarthritides of whatever joint distribution and associated syndromes, andrheumatic fever and its systemic complications; vasculitides includinggiant cell arteritis, Takayasu's arteritis, Churg-Strauss syndrome,polyarteritis nodosa, microscopic polyarteritis, and vasculitidesassociated with viral infection, hypersensitivity reactions,cryoglobulins, and paraproteins; low back pain; Familial Mediterraneanfever, Muckle-Wells syndrome, and Familial Hibernian Fever, Kikuchidisease; drug-induced arthalgias, tendonititides, and myopathies.

The compounds of formula (I) and their pharmaceutically acceptable saltscan also be used in the treatment of pain and connective tissueremodelling of musculoskeletal disorders due to injury [for example,sports injury] or disease: arthitides (for example rheumatoid arthritis,osteoarthritis, gout or crystal arthropathy), other joint disease (suchas intervertebral disc degeneration or temporomandibular jointdegeneration), bone remodelling disease (such as osteoporosis, Paget'sdisease or osteonecrosis), polychondritits, scleroderma, mixedconnective tissue disorder, spondyloarthropathies or periodontal disease(such as periodontitis).

The compounds of formula (I) and their pharmaceutically acceptable saltscan also be used in the treatment of diseases of skin such as psoriasis,atopic dermatitis, contact dermatitis or other eczematous dermatoses,and delayed-type hypersensitivity reactions; phyto- and photodermatitis;seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichensclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoidlupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa,urticaria, angioedema, vasculitides, toxic erythemas, cutaneouseosinophilias, alopecia greata, male-pattern baldness, Sweet's syndrome,Weber-Christian syndrome, erythema multiforme; cellulitis, bothinfective and non-infective; panniculitis; cutaneous lymphomas,non-melanoma skin cancer and other dysplastic lesions; drug-induceddisorders including fixed drug eruptions.

The compounds of formula (I) and their pharmaceutically acceptable saltscan also be used in the treatment of diseases of the eye such asblepharitis; conjunctivitis, including perennial and vernal allergicconjunctivitis; iritis; anterior and posterior uveitis; choroiditis;autoimmune; degenerative or inflammatory disorders affecting the retina;ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infectionsincluding viral, fungal, and bacterial.

The compounds of formula (I) and their pharmaceutically acceptable saltscan also be used in the treatment of diseases of the gastrointestinaltract such as glossitis, gingivitis, periodontitis; oesophagitis,including reflux; eosinophilic gastro-enteritis, mastocytosis, Crohn'sdisease, colitis including ulcerative colitis, proctitis, pruritis ani;coeliac disease, irritable bowel syndrome, non-inflammatory diarrhoea,and food-related allergies which may have effects remote from the gut(for example, migraine, rhinitis or eczema).

The compounds of formula (I) and their pharmaceutically acceptable saltscan also be used in the treatment of diseases of the cardiovascularsystem such as atherosclerosis, affecting the coronary and peripheralcirculation; pericarditis; myocarditis, inflammatory and auto-immunecardiomyopathies including myocardial sarcoid; ischaemic reperfusioninjuries; endocarditis, valvulitis, and aortitis including infective(for example syphilitic); vasculitides; disorders of the proximal andperipheral veins including phlebitis and thrombosis, including deep veinthrombosis and complications of varicose veins.

The compounds of formula (I) and their pharmaceutically acceptable saltscan also be used in oncology such as in the treatment of common cancersincluding prostate, breast, lung, ovarian, pancreatic, bowel and colon,stomach, skin and brain tumors and malignancies affecting the bonemarrow (including the leukaemias) and lymphoproliferative systems, suchas Hodgkin's and non-Hodgkin's lymphoma; including the prevention andtreatment of metastatic disease and tumour recurrences, andparaneoplastic syndromes.

In particular, the compounds of formula (I) and their pharmaceuticallyacceptable salts may be used in the treatment of adult respiratorydistress syndrome (ARDS), cystic fibrosis, pulmonary emphysema,bronchitis including chronic bronchitis, bronchiectasis, chronicobstructive pulmonary disease (COPD), pulmonary hypertension, asthmaincluding refractive asthma, rhinitis, psoriasis, ischemia-reperfusioninjury, rheumatoid arthritis, osteoarthritis, systemic inflammatoryresponse syndrome (SIRS), chronic wound, cancer, atherosclerosis, pepticulcers, Crohn' disease, ulcerative colitis and gastric mucosal injury.

More particularly, the compounds of formula (I) and theirpharmaceutically acceptable salts may be used in the treatment ofchronic obstructive pulmonary disease (COPD), asthma and rhinitis.

Even more particularly, the compounds of formula (I) and theirpharmaceutically acceptable salts may be used in the treatment ofchronic obstructive pulmonary disease (COPD).

Thus, the present invention provides a compound of formula (I) or apharmaceutically-acceptable salt thereof as hereinbefore defined for usein therapy.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined in the manufacture of a medicament for use intherapy.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined in the manufacture of a medicament for thetreatment of human diseases or conditions in which modulation ofneutrophil elastase activity is beneficial.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined in the manufacture of a medicament for use in thetreatment of an inflammatory disease or condition.

In a further aspect, the present invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined in the manufacture of a medicament for use intreating adult respiratory distress syndrome (ARDS), cystic fibrosis,pulmonary emphysema, bronchitis including chronic bronchitis,bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonaryhypertension, asthma including refractive asthma, rhinitis, psoriasis,ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis,systemic inflammatory response syndrome (SIRS), chronic wound, cancer,atherosclerosis, peptic ulcers, Crohn'disease, ulcerative colitis andgastric mucosal injury. In a further aspect, the present inventionprovides the use of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof as hereinbefore defined in the manufacture of amedicament for use in treating chronic obstructive pulmonary disease(COPD).

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disease or condition inquestion. Persons at risk of developing a particular disease orcondition generally include those having a family history of the diseaseor condition, or those who have been identified by genetic testing orscreening to be particularly susceptible to developing the disease orcondition.

The invention also provides a method of treating, or reducing the riskof, a disease or condition in which inhibition of neutrophil elastaseactivity is beneficial which comprises administering to a patient inneed thereof a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof as hereinbeforedefined.

The invention still further provides a method of treating, or reducingthe risk of, an inflammatory disease or condition which comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof as hereinbefore defined.

The invention still further provides a method of treating, or reducingthe risk of, adult respiratory distress syndrome (ARDS), cysticfibrosis, pulmonary emphysema, bronchitis including chronic bronchitis,bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonaryhypertension, asthma including refractive asthma, rhinitis, psoriasis,ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis,systemic inflammatory response syndrome (SIRS), chronic wound, cancer,atherosclerosis, peptic ulcers, Crohn'disease, ulcerative colitis andgastric mucosal injury which comprises administering to a patient inneed thereof a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof as hereinbeforedefined.

The invention still further provides a method of treating, or reducingthe risk of, chronic obstructive pulmonary disease (COPD) whichcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound of the invention may be in the range from 0.05 mg/kg to 100mg/kg.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used on their own but will generally be administered inthe form of a pharmaceutical composition in which the formula (I)compound/salt (active ingredient) is in association with apharmaceutically acceptable adjuvant, diluent or carrier. Conventionalprocedures for the selection and preparation of suitable pharmaceuticalformulations are described in, for example, “Pharmaceuticals—The Scienceof Dosage Form Designs”, M. E. Aulton, Churchill Livingstone, 1988.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (percent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof as hereinbefore defined, in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I) or a pharmaceutically acceptable salt thereof ashereinbefore defined with a pharmaceutically acceptable adjuvant,diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. tothe skin or to the lung and/or airways) in the form, e.g., of creams,solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powderformulations, for example, formulations in the inhaler device known asthe Turbuhaler®; or systemically, e.g. by oral administration in theform of tablets, capsules, syrups, powders or granules; or by parenteraladministration in the form of solutions or suspensions; or bysubcutaneous administration; or by rectal administration in the form ofsuppositories; or transdermally.

Dry powder formulations and pressurized HFA aerosols of the compounds ofthe invention may be administered by oral or nasal inhalation. Forinhalation, the compound is desirably finely divided. The finely dividedcompound preferably has a mass median diameter of less than 10 μm, andmay be suspended in a propellant mixture with the assistance of adispersant, such as a C₈-C₂₀ fatty acid or salt thereof, (for example,oleic acid), a bile salt, a phospholipid, an alkyl saccharide, aperfluorinated or polyethoxylated surfactant, or other pharmaceuticallyacceptable dispersant.

The compounds of the invention may also be administered by means of adry powder inhaler. The inhaler may be a single or a multi dose inhaler,and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound of the inventionwith a carrier substance, for example, a mono-, di- or polysaccharide, asugar alcohol, or another polyol. Suitable carriers are sugars, forexample, lactose, glucose, raffinose, melezitose, lactitol, maltitol,trehalose, sucrose, mannitol; and starch. Alternatively the finelydivided compound may be coated by another substance. The powder mixturemay also be dispensed into hard gelatine capsules, each containing thedesired dose of the active compound.

Another possibility is to process the finely divided powder into sphereswhich break up during the inhalation procedure. This spheronized powdermay be filled into the drug reservoir of a multidose inhaler, forexample, that known as the Turbuhaler® in which a dosing unit meters thedesired dose which is then inhaled by the patient. With this system theactive ingredient, with or without a carrier substance, is delivered tothe patient.

For oral administration the compound of the invention may be admixedwith an adjuvant or a carrier, for example, lactose, saccharose,sorbitol, mannitol; a starch, for example, potato starch, corn starch oramylopectin; a cellulose derivative; a binder, for example, gelatine orpolyvinylpyrrolidone; and/or a lubricant, for example, magnesiumstearate, calcium stearate, polyethylene glycol, a wax, paraffin, andthe like, and then compressed into tablets. If coated tablets arerequired, the cores, prepared as described above, may be coated with aconcentrated sugar solution which may contain, for example, gum arabic,gelatine, talcum and titanium dioxide. Alternatively, the tablet may becoated with a suitable polymer dissolved in a readily volatile organicsolvent.

For the preparation of soft gelatine capsules, the compound of theinvention may be admixed with, for example, a vegetable oil orpolyethylene glycol. Hard gelatine capsules may contain granules of thecompound using either the above-mentioned excipients for tablets. Alsoliquid or semisolid formulations of the compound of the invention may befilled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example, solutions containing the compound of theinvention, the balance being sugar and a mixture of ethanol, water,glycerol and propylene glycol. Optionally such liquid preparations maycontain colouring agents, flavouring agents, saccharine and/orcarboxymethylcellulose as a thickening agent or other excipients knownto those skilled in art.

The compounds of the invention may also be administered in conjunctionwith other compounds used for the treatment of the above conditions.

Thus, the invention further relates to combination therapies wherein acompound of the invention, or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition or formulation comprising acompound of the invention, is administered concurrently or sequentiallyor as a combined preparation with another therapeutic agent or agents,for the treatment of one or more of the conditions listed.

In particular, for the treatment of the inflammatory diseases such as(but not restricted to) rheumatoid arthritis, osteoarthritis, asthma,allergic rhinitis, chronic obstructive pulmonary disease (COPD),psoriasis, and inflammatory bowel disease, the compounds of theinvention may be combined with agents listed below.

Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) includingnon-selective cyclo-oxygenase COX-1/COX-2 inhibitors whether appliedtopically or systemically (such as piroxicam, diclofenac, propionicacids such as naproxen, flurbiprofen, fenoprofen, ketoprofen andibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac,azapropazone, pyrazolones such as phenylbutazone, salicylates such asaspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib,rofecoxib, valdecolib, lumarocoxib, parecoxib and etoricoxib);cyclo-oxygenase inhibiting nitric oxide donors (CINODs);glucocorticosteroids (whether administered by topical, oral,intramuscular, intravenous, or intra-articular routes); methotrexate;leflunomide; hydroxychloroquine; d-penicillamine; auranofin or otherparenteral or oral gold preparations; analgesics; diacerein;intra-articular therapies such as hyaluronic acid derivatives; andnutritional supplements such as glucosamine.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, together with a cytokine or agonist or antagonist of cytokinefunction, (including agents which act on cytokine signalling pathwayssuch as modulators of the SOCS system) including alpha-, beta-, andgamma-interferons; insulin-like growth factor type I (IGF-1);interleukins (IL) including IL1 to 23, and interleukin antagonists orinhibitors such as anakinra; tumour necrosis factor alpha (TNF-α)inhibitors such as anti-TNF monoclonal antibodies (for exampleinfliximab; adalimumab, and CDP-870) and TNF receptor antagonistsincluding immunoglobulin molecules (such as etanercept) andlow-molecular-weight agents such as pentoxyfylline. In addition theinvention relates to a combination of a compound of the invention, or apharmaceutically acceptable salt thereof, with a monoclonal antibodytargeting B-Lymphocytes (such as CD20 (rituximab), MRA-aIL16R andT-Lymphocytes, CTLA4-Ig, HuMax I1-15).

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, with a modulator of chemokine receptor function such as anantagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7,CCR8, CCR9, CCR10 and CCR11 (for the C—C family); CXCR1, CXCR2, CXCR3,CXCR4 and CXCR5 (for the C—X—C family) and CX₃CR1 for the C—X₃—C family.

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof, with aninhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, thecollagenases, and the gelatinases, as well as aggrecanase; especiallycollagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13),stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3(MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, and a leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO)inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist suchas; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761;a N-(5-substituted)-thiophene-2-alkylsulfonamide;2,6-di-tert-butylphenolhydrazones; a methoxytetrahydropyrans such asZeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted2-cyanonaphthalene compound such as L-739,010; a 2-cyanoquinolinecompound such as L-746,530; or an indole or quinoline compound such asMK-591, MK-886, and BAY x 1005.

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof, and areceptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4.selected from the group consisting of the phenothiazin-3-1s such asL-651,392; amidino compounds such as CGS-25019c; benzoxalamines such asontazolast; benzenecarboximidamides such as BIIL 284/260; and compoundssuch as zafirlukast, ablukast, montelukast, pranlukast, verlukast(MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, and a phosphodiesterase (PDE) inhibitor such as amethylxanthanine including theophylline and aminophylline; a selectivePDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of theisoform PDE4D, or an inhibitor of PDE5.

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof, and ahistamine type 1 receptor antagonist such as cetirizine, loratadine,desloratadine, fexofenadine, acrivastine, terfenadine, astemizole,azelastine, levocabastine, chlorpheniramine, promethazine, cyclizine, ormizolastine; applied orally, topically or parenterally.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, and a proton pump inhibitor (such as omeprazole) or agastroprotective histamine type 2 receptor antagonist.

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof, and anantagonist of the histamine type 4 receptor.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, and an alpha-1/alpha-2 adrenoceptor agonist vasoconstrictorsympathomimetic agent, such as propylhexedrine, phenylephrine,phenylpropanolamine, ephedrine, pseudoephedrine, naphazolinehydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, tramazoline hydrochlorideor ethylnorepinephrine hydrochloride.

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof, and ananticholinergic agents including muscarinic receptor (M1, M2, and M3)antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropiumbromide, tiotropium bromide, oxitropium bromide, pirenzepine ortelenzepine.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, and a beta-adrenoceptor agonist (including beta receptorsubtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol,terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or achiral enantiomer thereof.

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof, and aclromone, such as sodium cromoglycate or nedocromil sodium.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, with a glucocorticoid, such as flunisolide, triamcinoloneacetonide, beclomethasone dipropionate, budesonide, fluticasonepropionate, ciclesonide or mometasone furoate.

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof, with anagent that modulates a nuclear hormone receptor such as PPARs.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, together with an immunoglobulin (Ig) or Ig preparation or anantagonist or antibody modulating Ig function such as anti-IgE (forexample omalizumab).

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof, andanother systemic or topically-applied anti-inflammatory agent, such asthalidomide or a derivative thereof, a retinoid, dithranol orcalcipotriol.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, and combinations of aminosalicylates and sulfapyridine such assulfasalazine, mesalazine, balsalazide, and olsalazine; andimmunomodulatory agents such as the thiopurines, and corticosteroidssuch as budesonide.

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof,together with an antibacterial agent such as a penicillin derivative, atetracycline, a macrolide, a beta-lactam, a fluoroquinolone,metronidazole, an inhaled aminoglycoside; an antiviral agent includingacyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir,amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; aprotease inhibitor such as indinavir, nelfinavir, ritonavir, andsaquinavir; a nucleoside reverse transcriptase inhibitor such asdidanosine, lamivudine, stavudine, zalcitabine or zidovudine; or anon-nucleoside reverse transcriptase inhibitor such as nevirapine orefavirenz.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, and a cardiovascular agent such as a calcium channel blocker, abeta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE)inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agentsuch as a statin or a fibrate; a modulator of blood cell morphology suchas pentoxyfylline; thrombolytic, or an anticoagulant such as a plateletaggregation inhibitor.

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof, and aCNS agent such as an antidepressant (such as sertraline), ananti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole,pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comPinhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptakeinhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist oran inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer'sdrug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor,propentofylline or metrifonate.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, and an agent for the treatment of acute or chronic pain, suchas a centrally or peripherally-acting analgesic (for example an opioidor derivative thereof), carbamazepine, phenyloin, sodium valproate,amitryptiline or other anti-depressant agent-s, paracetamol, or anon-steroidal anti-inflammatory agent.

The present invention further relates to the combination of a compoundof the invention, or a pharmaceutically acceptable salt thereof,together with a parenterally or topically-applied (including inhaled)local anaesthetic agent such as lignocaine or a derivative thereof.

A compound of the present invention, or a pharmaceutically acceptablesalt thereof, can also be used in combination with an anti-osteoporosisagent including a hormonal agent such as raloxifene, or a biphosphonatesuch as alendronate.

The present invention still further relates to the combination of acompound of the invention, or a pharmaceutically acceptable saltthereof, together with a: (i) tryptase inhibitor; (ii) plateletactivating factor (PAF) antagonist; (iii) interleukin converting enzyme(ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitorsincluding VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor suchas an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, forexample Gefitinib or Imatinib mesylate), a serine/threonine kinase (suchas an inhibitor of a MAP kinase such as p38, JNK, protein kinase A, B orC, or IKK), or a kinase involved in cell cycle regulation (such as acylin dependent kinase); (viii) glucose-6 phosphate dehydrogenaseinhibitor; (ix) kinin-B.sub1.- or B.sub2.-receptor antagonist; (x)anti-gout agent, for example colchicine; (xi) xanthine oxidaseinhibitor, for example allopurinol; (xii) uricosuric agent, for exampleprobenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormonesecretagogue; (xiv) transforming growth factor (TGFβ); (xv)platelet-derived growth factor (PDGF); (xvi) fibroblast growth factorfor example basic fibroblast growth factor (bFGF); (xvii) granulocytemacrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream;(xix) tachykinin NK.sub1. or NK.sub3. receptor antagonist such asNKP-608C, SB-233412 (talnetant) or D-4418; (xx) elastase inhibitor suchas UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE);(xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii)chemoattractant receptor-homologous molecule expressed on TH2 cells,(such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agentmodulating the function of Toll-like receptors (TLR), (xxvi) agentmodulating the activity of purinergic receptors such as P2×7; or (xxvii)inhibitor of transcription factor activation such as NFkB, API, orSTATS.

A compound of the invention, or a pharmaceutically acceptable saltthereof, can also be used in combination with an existing therapeuticagent for the treatment of cancer, for example suitable agents include:

(i) an antiproliferative/antineoplastic drug or a combination thereof,as used in medical oncology, such as an alkylating agent (for examplecis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan or a nitrosourea); an antimetabolite (forexample an antifolate such as a fluoropyrimidine like 5-fluorouracil ortegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea,gemcitabine or paclitaxel); an antitumour antibiotic (for example ananthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin or mithramycin); anantimitotic agent (for example a vinca alkaloid such as vincristine,vinblastine, vindesine or vinorelbine, or a taxoid such as taxol ortaxotere); or a topoisomerase inhibitor (for example anepipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecanor a camptothecin);(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen,toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogenreceptor down regulator (for example fulvestrant), an antiandrogen (forexample bicalutamide, flutamide, nilutamide or cyproterone acetate), aLHRH antagonist or LHRH agonist (for example goserelin, leuprorelin orbuserelin), a progestogen (for example megestrol acetate), an aromataseinhibitor (for example as anastrozole, letrozole, vorazole orexemestane) or an inhibitor of 5α-reductase such as finasteride;(iii) an agent which inhibits cancer cell invasion (for example ametalloproteinase inhibitor like marimastat or an inhibitor of urokinaseplasminogen activator receptor function);(iv) an inhibitor of growth factor function, for example: a growthfactor antibody (for example the anti-erbb2 antibody trastuzumab, or theanti-erbb1 antibody cetuximab [C225]), a farnesyl transferase inhibitor,a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, aninhibitor of the epidermal growth factor family (for example an EGFRfamily tyrosine kinase inhibitor such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD 1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) or6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), an inhibitor of the platelet-derived growth factor family,or an inhibitor of the hepatocyte growth factor family;(v) an antiangiogenic agent such as one which inhibits the effects ofvascular endothelial growth factor (for example the anti-vascularendothelial cell growth factor antibody bevacizumab, a compounddisclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or acompound that works by another mechanism (for example linomide, aninhibitor of integrin αvβ3 function or an angiostatin);(vi) a vascular damaging agent such as combretastatin A4, or a compounddisclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO02/04434 or WO 02/08213;(vii) an agent used in antisense therapy, for example one directed toone of the targets listed above, such as ISIS 2503, an anti-rasantisense;(viii) an agent used in a gene therapy approach, for example approachesto replace aberrant genes such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme and approaches to increase patient tolerance tochemotherapy or radiotherapy such as multi-drug resistance gene therapy;or(ix) an agent used in an immunotherapeutic approach, for example ex-vivoand in-vivo approaches to increase the immunogenicity of patient tumourcells, such as transfection with cytokines such as interleukin 2,interleukin 4 or granulocyte-macrophage colony stimulating factor,approaches to decrease T-cell anergy, approaches using transfectedimmune cells such as cytokine-transfected dendritic cells, approachesusing cytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

In particular the compounds of the invention may be administered inconjunction with a second active ingredient which is selected from:

-   -   a) a PDE4 inhibitor including an inhibitor of the isoform PDE4D;    -   b) a β-adrenoceptor agonist such as metaproterenol,        isoproterenol, isoprenaline, albuterol, salbutamol, formoterol,        salmeterol, terbutaline, orciprenaline, bitolterol mesylate,        pirbuterol or indacaterol;    -   c) a muscarinic receptor antagonist (for example a M1, M2 or M3        antagonist, such as a selective M3 antagonist) such as        ipratropium bromide, tiotropium bromide, oxitropium bromide,        pirenzepine or telenzepine;    -   d) a modulator of chemokine receptor function (such as a CCR1 or        CCR8 receptor antagonist);    -   e) an inhibitor of kinase function;    -   f) a non-steroidal glucocorticoid receptor agonist;    -   g) a steroidal glucocorticoid receptor agonist; and    -   h) a protease inhibitor (such as a MMP12 or MMP9 inhibitor);

The present invention will now be further explained by reference to thefollowing illustrative examples.

General Methods

¹H NMR and ¹³C NMR spectra were recorded on a Varian Inova 400 MHz or aVarian Mercury-VX 300 MHz instrument. The central peaks of chloroform-d(δ_(H) 7.27 ppm), dimethylsulfoxide-d₆ (δ_(H) 2.50 ppm), acetonitrile-d₃(δ_(H) 1.95 ppm) or methanol-d₄ (δ_(H) 3.31 ppm) were used as internalreferences. Column chromatography was carried out using silica gel(0.040-0.063 mm, Merck). Unless stated otherwise, starting materialswere commercially available. All solvents and commercial reagents wereof laboratory grade and were used as received.

The following method was used for LC/MS analysis:

Instrument Agilent 1100; Column Waters Symmetry 2.1×30 mm; Mass APCI;Flow rate 0.7 ml/min; Wavelength 254 nm; Solvent A: water+0.1% TFA;Solvent B: acetonitrile+0.1% TFA; Gradient 15-95%/B 8 min, 95% B 1 min.

Analytical chromatography was run on a Symmetry C₁₈-column, 2.1×30 mmwith 3.5 μm particle size, with acetonitrile/water/0.1% trifluoroaceticacid as mobile phase in a gradient from 5% to 95% acetonitrile over 8minutes at a flow of 0.7 ml/min.

The abbreviations or terms used in the examples have the followingmeanings:

THF: Tetrahydrofuran DCM: Dichloromethane DME: Dimethoxyethane DMF:N,N-Dimethylformamide

EtOAc: Ethyl acetateDMSO: Dimethyl sulphoxideSM: Starting material

Ex: Example

RT: Room temperature

EXAMPLE 16-[2-(4-Cyano-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylicacid methylamide

6-Bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide(SM2, 0.05 g, 0.128 mmol), 1-(4-cyanophenyl)-1H-pyrazol-5-boronic acid(SM4, 0.062 g, 0.256 mmol), Cs₂CO₃ (0.125 g, 0.384 mmol) and DME (3 ml)were added to a glass tube for microwave synthesis. The mixture wasdegassed with nitrogen and Pd(PBu^(t) ₃)₂ (0.010 g) was added. The tubewas sealed and heated with stirring at 110° C. (150 W) in a microwaveheater for 10 minutes. The mixture was diluted with EtOAc (5 ml), andfiltered. The solution was concentrated in vacuo and was purified bychromatography on silica to give a reasonably pure material that wasfurther purified by preparative HPLC to give 0.012 g (20%) of the titlecompound as a white solid.

¹H NMR (400 MHz, DMSO-D₆) δ 8.70 (m, 1H), 7.97-7.84 (m, 6H), 7.77 (d,J=7.8 Hz, 1H); 7.67 (d, J=8.8 Hz, 2H), 6.76 (d, J=1.8 Hz, 1H), 2.72 (d,J=4.8 Hz, 3H), 1.86 (s, 3H);

APCI-MS m/z: 479.3 [MH⁺].

EXAMPLES 2 AND 3

The following compounds were synthesised in an analogous manner toExample 1.

Ex Compound ¹H NMR m/z SM 2 6-[2-(4-Cyano-phenyl)-2H- ¹H NMR (400 MHz,DMSO-D₆) δ 634.0 SM3 pyrazol-3-yl]-5-methyl-3- 9.52 (t, J = 6.0 Hz, 1H),8.98 (bs, SM4 oxo-4-(3-trifluoromethyl- 1H), 8.27 (d, J = 8.2 Hz, 1H),8.00- phenyl)-3,4-dihydro- 7.85 (m, 6H), 7.81 (d, J = 8.3 Hz,pyrazine-2-carboxylic acid 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.49(5-methanesulfonyl-pyridin- (d, J = 8.3 Hz, 1H), 6.79 (s, 1H),2-ylmethyl)-amide 4.63 (d, J = 6.0 Hz, 2H), 3.29 (s, 3H), 1.91 (s, 3H).3 6-[2-(4-Cyano-phenyl)-2H- ¹H NMR (400 MHz, DMSO-D₆) δ 493.1 SM4pyrazol-3-yl]-5-methyl-3- 8.69 (t, J = 5.7 Hz, 1H), 7.98-7.84 (m,oxo-4-(3-trifluoromethyl- 6H), 7.77 (d, J = 8.0 Hz, 1H), 7.67phenyl)-3,4-dihydro- (d, J = 8.8 Hz, 2H), 6.77 (d, J = 1.8pyrazine-2-carboxylic acid Hz, 1H), 3.24-3.16 (m, 2H), 1.87 (s,ethylamide 3H), 1.02 (t, J = 7.2 Hz, 3H).

EXAMPLE 46-[1-(4-Cyano-phenyl)-1H-1,2,3-triazol-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydro-pyrazine-2-carboxamidea) 4-[1,2,3]Triazol-1-yl-benzonitrile

4-Fluorobenzonitrile (0.847 g, 7 mmol), 1H-[1,2,3]triazole (0.483 g, 7mmol), Cs₂CO₃ (2.27 g, 7 mmol) and DMF (8 ml) and a magnetic stirrerwere placed in a vial. The mixture was heated with stirring for 3 h at80° C. Extractive work-up (EtOAc/H₂O) and subsequent drying (Na₂SO₄)gave a crude product which was purified on silica giving 0.55 g (46%) ofthe title intermediate.

¹H NMR (400 MHz, DMSO-D₆) δ 9.00 (d, J=1.2 Hz, 1H), 8.18 (d, J=8.8 Hz,2H), 8.11 (d, J=8.8 Hz, 2H), 8.05 (d, J=1.2 Hz, 1H).

b) 4-(5-Tributylstannanyl-[1,2,3]-triazol-1-yl)-benzonitrile

4-[1,2,3]Triazol-1-yl-benzonitrile (0.105 g, 0.6 mmol) and dry THF (6ml) and a magnetic stirrer were placed in a flask. The flask was flushedwith argon and kept under an inert atmosphere and cooled to −78° C. Atthis temperature, tert-BuLi (0.36 ml, 1.7M, 0.6 mmol) was added dropwiseduring 1-2 minutes. The mixture was stirred at this temperature for 15minutes and Bu₃SnCl (0.19 g, 0.6 mmol) was added during 1 minute, andthe mixture was then allowed to slowly reach RT. The crude mixture wasdirectly purified on silica (heptane:EtOAc 4:1) giving 0.12 g (43%) ofthe title stannane.

APCI MS m/z: 460 [MH⁺].

c)6-[1-(4-Cyano-phenyl)-1H-1,2,3-triazol-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydro-pyrazine-2-carboxamide

4-(5-Tributylstannanyl-[1,2,3]triazol-1-yl)-benzonitrile (0.15 g, 0.32mmol),6-bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide(SM2, 0.054 g, 0.14 mmol), Pd(PBu^(t) ₃)₂ (10 mg) and DME (2 ml) wereplaced in a tube for microwave synthesis. The mixture was degassed withargon and heated in a synthesis microwave heater (CEM) at 100° C. (max150 W) for 10 minutes. The solvent was removed in vacuo giving a crudeproduct which was purified on silica and then further purified onpreparative HPLC. The pure fractions were freeze-dried giving 27 mg(41%) of the title compound.

¹H NMR (400 MHz, DMSO-D₆) δ 8.64-8.57 (m, 1H), 8.18 (s, 1H), 8.02 (d,J=8.4 Hz, 2H), 7.98-7.92 (m, 2H), 7.88 (t, J=8.0 Hz, 1H), 7.83 (d, J=8.4Hz, 2H), 7.77 (d, J=8.0 Hz, 1H), 2.70 (d, J=4.9 Hz, 3H), 1.94 (s, 3H).

APCI-MS m/z: 480.0 [MH⁺].

EXAMPLES 5 TO 9

The following compounds were synthesised in an analogous manner toExample 4.

Ex Compound ¹H NMR m/z SM 5 tert-Butyl 2-[[6-[2-(4- ¹H NMR (400 MHz,DMSO-D₆) δ 579.4 cyanophenyl)pyrazol-3-yl]-5- 9.17 (t, J = 5.7 Hz, 1H),7.96 (d, J = methyl-3-oxo-4-[3- 6.7 Hz, 2H), 7.94 (d, J = 1.8 Hz, 1H),(trifluoromethyl)phenyl]-3,4- 7.92-7.85 (m, 3H), 7.80 (d, J = 7.8dihydro-pyrazine-2- Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H),carbonyl]amino]acetate 6.78 (d, J = 1.8 Hz, 1H), 3.89 (d, J = 5.8 Hz,2H), 1.90 (s, 3H), 1.39 (s, 9H). 6 6-[3-(4-Chloro-phenyl)-3H- ¹H NMR(400 MHz, DMSO-D₆) δ 489.3 SM2 [1,2,3]triazol-4-yl]-5-methyl- 8.65-8.57(m, 1H), 8.13 (s, 1H), 3-oxo-4-(3-trifluoromethyl- 7.98-7.91 (m, 2H),7.87 (t, J = 7.9 Hz, phenyl)-3,4-dihydro- 1H), 7.76 (d, J = 7.9 Hz, 1H),7.65 (d, pyrazine-2-carboxylic acid J = 8.9 Hz, 2H), 7.59 (d, J = 8.9Hz, methylamide 2H), 2.72 (d, J = 4.7 Hz, 3H), 1.89 (s, 3H). 76-[2-(4-Chloro-phenyl)-2H- ¹H NMR (400 MHz, DMSO-D₆) δ 488.0 SM2pyrazol-3-yl]-5-methyl-3- 8.74-8.65 (m, 1H), 8.01-7.68 (m,oxo-4-(3-trifluoromethyl- 6H), 7.62-7.44 (m, 3H), 7.60 (d,phenyl)-3,4-dihydro- J = 1.8 Hz, 1H), 2.73 (d, J = 4.8 Hz,pyrazine-2-carboxylic acid 3H), 1.80 (s, 3H). methylamide 86-[1-(4-Cyanophenyl)-1H- ¹H NMR (400 MHz, CD₃CN) δ 9.01 523.0pyrazol-5-yl]-N-(2- (s, 1H), 7.90 (d, J = 7.3 Hz, 1H),methoxyethyl)-5-methyl-3- 7.80 (m, 4H), 7.63 (m, 4H), 6.68 (d, oxo-4-[3-J = 1.8 Hz, 1H), 3.47 (m, 2H), 3.31 (trifluoromethyl)phenyl]-3,4- (d, J= 9.7 Hz, 5H), 1.86 (s, 3H). dihydropyrazine-2- carboxamide 96-[1-(4-Cyanophenyl)-1H- ¹H NMR (400, CD₃CN) δ 8.98 (s, 537.1pyrazol-5-yl]-N-(2-hydroxy- 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.841,1-dimethylethyl)-5-methyl- (d, J = 1.6 Hz, 2H), 7.79 (s, 2H),3-oxo-4-[3- 7.61 (t, J = 8.7 Hz, 4H), 6.68 (d, J =(trifluoromethyl)phenyl]-3,4- 1.6 Hz, 1H), 3.49 (s, 2H), 1.86 (s,dihydropyrazine-2- 3H), 1.27 (d, J = 10.6 Hz, 6H). carboxamide

EXAMPLE 106-[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamidea)5-Methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylicacid

NaOH (1M, 6 ml) was added to methyl5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate(0.60 g, 1.92 mmol) dissolved in EtOH (12 ml) and the to mixture wasstirred for 15 minutes. The aqueous phase was neutralized by addition ofHCl (1M, 7 ml) to pH 6 to 7 and extracted with ethyl acetate (3×15 ml).The organic phase was dried (MgSO4), filtered and evaporated. No furtherpurification was performed.

APCI-MS m/z: 299.0 [MH⁺].

b)N,N,5-Trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

A mixture of5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylicacid (0.21 g, 0.7 mmol), HATU (0.266 g, 0.7 mmol) and Et₃N (0.293 g, 2.9mmol) in DMF (2 ml) was reacted with dimethylamine HCl. After 2 h, thereaction mixture was diluted with water and extracted with ethyl acetate(3×5 ml). The organic phase was dried (MgSO₄), filtered and evaporated.No further purification was performed.

APCI-MS m/z: 326.0 [MH⁺].

c)6-Bromo-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

N,N,5-Trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide(0.14 g, 0.43 mmol) was dissolved under argon in DMF (2 ml) in a vial.N-Bromosuccinimide (0.089 g, 0.5 mmol) was added. The vial was sealedand stirred for 30 minutes. The crude mixture was purified onpreparative HPLC to give 0.100 g (57%) of the title compound as a solid.

APCI-MS m/z: 403.9 [MH⁺].

d)6-(3,3-Diethoxyprop-1-ynyl)-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

6-Bromo-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide(0.10 g, 0.247 mmol), propargylaldehyde diethyl acetal (0.48 mg, 0.370mmol), copper(I) iodide (0.001 mg, 0.005 mmol) and Et₃N (1 ml) in THF (1ml) were placed in a glass tube for microwave synthesis. The mixture wasdegassed with argon and Pd(Cl₂) (PPh₃)₂ (0.007 g) was added. The tubewas sealed and heated with stirring at 60° C. (150 W) in a microwaveheater for 20 minutes. The mixture was diluted with EtOAc (5 ml) andfiltered. The solution was concentrated in vacuo and was then purifiedon silica to give the title compound (28 mg, 25%).

e)6-[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethylphenyl]-3,4-dihydropyrazine-2-carboxamide

6-(3,3-Diethoxyprop-1-ynyl)-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide(0.028 g, 0.062 mmol) was dissolved in DMF (1 ml) in a microwave vial.4-Cyanophenylhydrazine hydrochloride (0.013 g, 0.074 mmol) was added.The vial was sealed and heated with stirring to 120° C. for 5 minutes.The crude mixture was purified on preparative HPLC to give 9 mg (29%) ofthe title compound as a white solid.

¹H NMR (399.99 MHz, CD₃CN) δ 7.88 (d, J=7.8 Hz, 1H), 7.79 (m, 5H), 7.64(m, 3H), 6.64 (d, J=1.8 Hz, 1H), 2.90 (d, J=8.8 Hz, 3H), 2.70 (s, 3H),1.97 (s, 3H).

APCI-MS m/z: 493.0 [MH⁺].

EXAMPLE 11

The following compound was synthesised in an analogous manner to Example10.

Ex Compound ¹H NMR m/z 11 6-[1-(4-Cyanophenyl)-1H- ¹H NMR (400 MHz,CD₃CN) δ 8.80 505.0 pyrazol-5-yl]-N-cyclopropyl- (s, 1H), 7.97 (d, 1H),7.93-7.86 (m, 5-methyl-3-oxo-4-[3- 4H), 7.72 (t, 3H), 7.67 (s, 1H), 6.76(trifluoromethyl)phenyl]-3,4- (d, J = 1.8 Hz, 1H), 2.93 (dq, J = 7.3,dihydropyrazine-2- 3.7 Hz, 1H), 1.95 (s, 3H), 0.83 (dd, carboxamide J =7.0, 1.7 Hz, 2H), 0.59 (dd, J = 10.6, 5.0 Hz, 2H).

EXAMPLE 126-[1-(6-Cyanopyridin-3-yl)-1H-pyrazol-5yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamidea) Methyl6-iodo-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate

Methyl5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate(described in the synthesis of SM2, 1.5 g, 4.8 mmol), dry DCM (7.0 mL),trifluoroacetic acid (3.0 mL) and N-iodosuccinimide (1.0 g, 4.5 mmol)were mixed and stirred at RT in the dark (flask covered with aluminumfoil). After 5 h, water (5 mL) was added and the mixture wasconcentrated by rotary evaporation. Water (3 mL) was added once more andthe mixture was concentrated as described above. The resulting mixturewas diluted with acetonitrile to a total volume of 50 mL. Purificationby preparative HPLC with acetonitrile-water as eluent (neutral eluent)gave 0.905 g (46% yield) of the title compound as a yellow crystallinesolid.

¹H NMR (400 MHz, DMSO-D₆) δ 7.93 (br s, 1H), 7.92 (d, J=7.6 Hz, 1H),7.84 (t, J=7.6 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 3.82 (s, 3H), 2.14 (s,3H).

APCI-MS m/z 438.8 (MH⁺).

b) Methyl6-(3,3-diethoxyprop-1′-ynyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate

Methyl6-iodo-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate(1.2 g, 2.8 mmol), allylpalladium(II) chloride dimer (0.0072 g), 10% byweight tri(tert-butyl)phosphine in hexane (2.1 mL) and anhydrous DMF(3.0 mL) were stirred until a clear solution was obtained.Propargylaldehyde diethyl acetal (0.44 mL, 3.1 mmol) in anhydrous DMF(2.3 mL) was added, followed by 1,4-diazabicyclo[2.2.2]octane (0.63 g,5.6 mmol) in small portions. The red solution was purged with dry argonfor 5 minutes and then stirred under argon at RT. After 4 h, the solventwas evaporated using an oil pump. The residue was taken up inacetonitrile (10 mL), filtered through glass-wool and then concentratedwith silica. Chromatography on silica with ethyl acetate-heptanes (1:10and 1:2) as eluents gave 0.46 g (37%) of the title compound as a yellowoil.

¹H NMR (400 MHz, CD₂Cl₂) δ 7.84 (d, J=8.8 Hz, 1H), 7.77 (d, J=8.0 Hz,1H), 7.49 (br s, 1H), 7.43 (d, J=8.4 Hz, 1H), 5.47 (s, 1H), 3.92 (s,3H), 3.80-3.71 (m, 2H), 3.68-3.58 (m, 2H), 2.20 (s, 3H), 1.23 (t, J=7.2Hz, 6H).

APCI-MS m/z 439 (MH⁺), 393 (M-45).

c) Methyl6-[1-(6-cyanopyridin-3-yl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate

Methyl6-(3,3-diethoxyprop-1-ynyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate(0.073 g, 0.17 mmol) and 5-hydrazinopyridine-2-carbonitriletrifluoroacetate (0.050 g, 0.20 mmol) in dioxane (3 ml) were placed in avial. 2M HCl (0.188 ml) was added and the mixture was stirred at 55° C.for 15 min. After cooling, NaHCO₃ (0.048 g) was added and the mixturewas extracted with DCM and water. The combined organic phases werewashed with water, brine, dried (Na₂SO₄) and evaporated. The residue wasdissolved in acetic acid (10 ml) and the vial was sealed. The solutionwas stirred at 90° C. for 10 h. After evaporation, the residue waspurified by preparative HPLC to give 0.023 g (28%) of the titlecompound.

APCI-MS m/z: 481.0 [MH⁺].

d)6-[1-(6-Cyanopyridin-3-yl)-1H-pyrazol-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

Methyl6-[1-(6-cyanopyridin-3-yl)-1H-pyrazol-5-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate(0.026 g, 0.054 mmol) in acetonitrile (0.33 ml) and ethanol (0.074 ml)were placed in a vial. Cyclopropylamine (0.14 ml, 2.0 mmol) was added,the vial sealed and stirred at 60° C. for 10 h. After evaporation, theresidue was purified by preparative HPLC to give 0.010 g (37%) of thetitle compound.

¹H NMR (400 MHz, DMSO-D₆) δ 8.89 (d, J=2.3 Hz, 1H), 8.69 (d, J=4.5 Hz,1H), 8.18-8.09 (m, 2H), 8.01-7.93 (m, 3H), 7.88 (t, J=8.0 Hz, 1H), 7.79(d, J=7.9 Hz, 1H), 6.82 (d, J=1.8 Hz, 1H), 2.79-2.69 (m, 1H), 2.03 (s,3H), 0.71-0.62 (m, 2H), 0.45-0.36 (m, 2H).

APCI-MS m/z: 506.0 [MH].

EXAMPLES 13 TO 15

The following compounds were synthesised in an analogous manner toExample 12.

Ex Compound ¹H NMR m/z SM 13 6-[1-(6-Cyanopyridin-3-yl)- ¹H NMR (400MHz, DMSO-D₆) δ 480.0 1H-pyrazol-5-yl]-N,5- 8.91 (d, J = 2.3 Hz, 1H),8.76-8.68 dimethyl-3-oxo-4-[3- (m, 1H), 8.20-8.09 (m, 2H), 8.02-(trifluoromethyl)phenyl]-3,4- 7.93 (m, 3H), 7.89 (t, J = 7.8 Hz,dihydropyrazine-2- 1H), 7.81 (d, J = 8.0 Hz, 1H), 6.82 carboxamide (d, J= 1.7 Hz, 1H), 2.70 (d, J = 4.6 Hz, 3H), 2.02 (s, 3H). 146-[1-(5-Cyanopyridin-2-yl)- ¹H NMR (400 MHz, DMSO-D₆) δ 480.01H-pyrazol-5-yl]-N,5- 8.88-8.81 (m, 2H), 8.45 (dd, J =dimethyl-3-oxo-4-[3- 8.6, 2.2 Hz, 1H), 8.08 (d, J = 8.5 Hz,(trifluoromethyl)phenyl]-3,4- 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.99-dihydropyrazine-2- 7.94 (m, 2H), 7.89 (t, J = 8.1 Hz, carboxamide 1H),7.81 (d, J = 7.7 Hz, 1H), 6.80 (d, J = 1.6 Hz, 1H), 2.73 (d, J = 4.7 Hz,3H), 1.84 (s, 3H). 15 6-[1-(5-Cyanopyridin-2-yl)- ¹H NMR (400 MHz,DMSO-D₆) δ 506.0 1H-pyrazol-5-yl]-N- 8.95 (d, J = 4.4 Hz, 1H), 8.85 (d,J = cyclopropyl-5-methyl-3-oxo- 1.7 Hz, 1H), 8.45 (dd, J = 8.7, 2.14-[3- Hz, 1H), 8.07 (d, J = 8.9 Hz, 1H), (trifluoromethyl)phenyl]-3,4-8.02 (d, J = 1.6 Hz, 1H), 7.99-7.94 dihydropyrazine-2- (m, 2H), 7.88 (t,J = 8.1 Hz, 1H), carboxamide 7.80 (d, J = 7.9 Hz, 1H), 6.80 (d, J = 1.6Hz, 1H), 2.84-2.75 (m, 1H), 1.85 (s, 3H), 0.72-0.65 (m, 2H), 0.49-0.43(m, 2H).

EXAMPLE 162-[[6-[2-(4-Cyanophenyl)pyrazol-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazine-2-carbonyl]amino]aceticacid

The title compound was obtained from Example 5 after acidic cleavage ofthe t-butyl ester and HPLC purification.

¹H NMR (400 MHz, DMSO-D₆) δ 12.71 (s, 1H), 9.25 (t, J=5.6 Hz, 1H), 7.96(d, J=6.2 Hz, 2H), 7.94 (d, J=1.8 Hz, 1H), 7.92-7.85 (m, 3H), 7.80 (d,J=8.0 Hz, 1H), 7.68 (d, J=9.3 Hz, 2H), 6.78 (d, J=1.8 Hz, 1H), 3.94 (d,J=5.5 Hz, 2H), 1.88 (s, 3H).

APCI-MS m/z: 523.3 [MH⁺].

Preparation of Starting Materials

The starting materials for the examples above are either commerciallyavailable or are readily prepared by standard methods from knownmaterials. For example, the following reactions are illustrations, butnot a limitation, of the preparation of some of the starting materials.

Starting Material SM13-Bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]pyrazin-2(1H)-one

3-Trifluoromethylaniline (5.0 g, 31 mmol) and triethylamine (3.54 g, 35mmol) were dissolved in DCM (60 ml, dried). The mixture was cooled onice and to the stirred solution was added dropwise a solution of ethyloxalyl chloride (4.36 g, 32 mmol) in DCM (15 ml). After completeaddition, the reaction was allowed to stand for 10 minutes. The reactionmixture was washed with water (50 ml), then washed with brine (30 ml),and the organic phase was dried over Na₂SO₄. Filtration and evaporationgave 8.04 g (99%) of ethyl oxo {[3-(trifluoromethyl)phenyl]amino}acetateas a white solid.

¹H NMR (300 MHz, DMSO-D₆) δ 11.09 (s, 1H), 8.19 (s, 1H), 8.03 (d, J=8.0Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 4.32 (q, J=7.5Hz, 2H), 1.32 (t, J=7.0 Hz, 3H);

APCI-MS m/z: 262.0 [MH⁺].

Ethyl oxo{[3-(trifluoromethyl)-phenyl]amino}acetate (8.04 g, 30.7 mmol)was dissolved in ethanol (50 ml, 99.5%). To the stirred solution wasadded 1-amino-2-propanol (racemic, 2.32 g, 31 mmol) in one portion, andthe mixture was heated to reflux for 90 minutes. The mixture was allowedto cool and was evaporated to dryness, giving 8.80 g (99%) ofN-(2-hydroxypropyl)-N′-[3-(trifluoromethyl)-phenyl]ethanediamide as awhite solid.

¹H NMR (300 MHz, DMSO-D₆) δ 10.99 (bs, 1H), 8.77 (t, J=6.3 Hz, 1H), 8.29(s, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.60 (t, J=8.1 Hz, 1H), 7.49 (d, J=7.5Hz, 1H), 4.91 (d, J=4.9 Hz, 1H), 3.78 (p, J=5.7 Hz, 1H), 3.20-3.12 (m,2H), 1.05 (d, J=6.3 Hz, 3H);

APCI-MS m/z: 273.1 [MH⁺−18].

N-(2-Hydroxypropyl)-N′-[3-(trifluoromethyl)phenyl]-ethanediamide (2.2 g,7.58 mmol) was dissolved in CH₃CN (50 ml) and water (7 ml). To thestirred solution was added NaBrO₃ (1.15 g, 7.58 mmol) and a solution ofRuCl₃xH₂O in CH₃CN (3 ml). The mixture was stirred for 1 h, and thereaction was monitored by IC-MS and TLC. The organic solvent was removedin vacuo, and the residue was partitioned between DCM (200 ml) and water(200 ml). The organic phase was dried with Na₂SO₄ and upon filtrationand evaporation 2.0 g (91%) ofN-(2-oxopropyl)-N′-[3-(trifluoromethyl)phenyl]ethanediamide was obtainedas a grey-white solid.

¹H NMR (300 MHz, DMSO-D₆) δ 11.04 (s, 1H), 9.08 (t, J=6.0 Hz, 1H), 8.29(s, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.50 (d, J=7.9Hz, 1H), 4.09 (d, J=6.0 Hz, 2H), 2.14 (s, 3H).

N-(2-Oxopropyl)-N′-[3-(trifluoromethyl)phenyl]ethanediamide (1.6 g, 5.5mmol) and glacial acetic acid (15 ml) were placed in a vial (20 ml). Tothis solution was added concentrated sulfuric acid (40 drops), and theflask was sealed, and heated with stirring to 100° C. for 90 minutes.Another 40 drops of sulfuric acid was added, and the reaction wasallowed to proceed for another 90 minutes. The reaction mixture wasallowed to cool, and acetic acid was removed in vacuo. The residue waspartitioned between EtOAc (60 ml) and water (40 ml). The aqueous phasewas neutralized by addition of NaOH solution to pH 6 to 7. The organicphase was dried, and upon filtration and evaporation a crude product wasobtained, which was purified on silica giving 1.1 g (74%) of6-methyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyrazine-2,3-dione asa yellowish solid.

¹H NMR (400 MHz, DMSO-D₆) δ 11.24 (bs, 1H), 7.87-7.81 (m, 2H), 7.77 (t,J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 6.30 (d, J=5.2 Hz, 1H), 1.61 (d,J=1.1 Hz, 3H); APCI-MS m/z: 271.0 [MH⁺].

6-Methyl-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyrazine-2,3-dione(0.52 g, 1.92 mmol) and 1,2-dichloroethane (10 ml) were placed in a vial(20 ml). To the resulting suspension was added carefully oxalyl bromide(0.53 ml, 1.24 g, 5.75 mmol). A foam was formed during the addition, andas the foam was settling down the stirring was started. DMF (3 drops)was added and the vial was sealed and the mixture was stirred overnight.Another portion of oxalyl bromide (0.2 ml, 0.46 g, 2.23 mmol) and DMF (3drops) was added and the reaction was run for another 24 h. The mixturewas partitioned between DCM (20 ml) and water (20 ml) and the organicphase was dried. Filtration and evaporation gave a crude product, whichwas purified on silica, affording 0.59 g (93%) of3-bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]pyrazin-2(1H)-one.

¹H NMR (400 MHz, DMSO-D₆) δ 7.96 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.83(t, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.27 (s, 1H), 1.84 (s, 3H);APCI-MS m/z: 232.9 and 234.9 [MH⁺].

Starting Material SM2 6-Bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethylphenyl]-3,4-dihydropyrazine-2-carboxamide

A high-pressure steel reactor (Parr) with CO-gas inlet was charged with3-bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]pyrazin-2(1H)-one (SM1,0.25 g, 0.75 mmol), Pd(OAc)₂ (0.015 g, 0.067 mmol), PPh₃ (0.030 g, 0.11mmol) and methanol (25 ml). To this mixture was added triethylamine (0.5ml, 0.36 g, 3.6 mmol) and a magnetic stirrer bar. The reactor wasventilated with CO, and 6 atmospheres CO-pressure was applied to thesystem. The reactor was heated with stirring to 90° C., and the mixturewas stirred vigorously and the reaction was allowed to proceed for 4 h.The volatiles were removed in vacuo and the crude product was purifiedon silica, to give 0.11 g (47%) of methyl5-methyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydropyrazine-2-carboxylateas a solid.

¹H NMR (400 MHz, DMSO-D₆) δ 7.97 (s, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.83(t, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.52 (s, 1H), 3.80 (s, 3H),1.94 (s, 3H);

APCI-MS m/z: 313.0 [MH⁺].

Methyl5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylate(0.11 g, 0.35 mmol) was dissolved in a solution of methylamine (33% inethanol, 5 ml) in a vial. The vial was sealed and heated with stirringat 50° C. for 30 minutes. The volatiles were removed in vacuo giving acrude product which was purified for analytical purposes on preparativeHPLC to give 0.079 g (73%) ofN,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamideas a solid.

¹H NMR (400 MHz, DMSO-D₆) δ 8.95 (m, 1H), 7.98-7.90 (m, 2H), 7.84 (t,J=7.7 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.64 (s, 1H), 2.78 (d, J=4.7 Hz,3H), 1.98 (s, 3H);

APCI-MS m/z: 312.0 [MH⁺].

N,5-Dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide(0.079 g, 0.25 mmol) was dissolved in DMF (1.5 ml) in a vial.N-Bromosuccinimide (0.066 g, 0.38 mmol) was added. The vial was sealedand heated with stirring to 50° C. for 90 minutes. The crude mixture wasadded dropwise to water (20 ml) under magnetic stirring. The precipitatewas isolated by filtration to give 0.078 g (80%) of6-bromo-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamideas a solid.

¹H NMR (400 MHz, DMSO-D₆) δ 8.96 (m, 1H), 7.98-7.91 (m, 2H), 7.86 (t,J=8.2 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 2.79 (d, J=4.8 Hz, 3H), 2.12 (s,3H); APCI-MS m/z: 389.9 and 391.9 [MH⁺].

Starting Material SM36-Bromo-5-methyl-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide

A high-pressure steel reactor (Parr) with CO-gas inlet was charged with3-bromo-6-methyl-1-[3-(trifluoromethyl)phenyl]pyrazin-2(1H)-one (SM1,0.30 g, 0.89 mmol), Pd(OAc)₂ (0.035 g, 0.16 mmol), PPh₃ (0.070 g, 0.26mmol) and 5-methanesulfonyl-pyridine-2-ylamine (0.46 g, 1.79 mmol) inmethanol (25 ml). To this mixture was added triethylamine (1.5 ml, 1.09g, 10 mmol) and a magnetic stirrer bar. The reactor was ventilated withCO and 6 atmospheres CO-pressure was applied to the system. The reactorwas heated to 90° C., the mixture was vigorously stirred, and thereaction was allowed to proceed for 4 h, and was then allowed to cool.The volatiles were removed in vacuo and the crude product was purifiedby preparative HPLC, which gave 0.22 g (53%) of5-methyl-N-{[5-(methylsulfonyl)-pyridin-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydropyrazine-2-carboxamideas a white solid, after freeze-drying the pure fractions.

¹H NMR (400 MHz, DMSO-D₆) δ 9.81 (t, J=5.8 Hz, 1H), 8.99 (d, J=2.15 Hz,1H), 8.29 (dd, J=8.3 and 2.3 Hz, 1H), 7.98 (s, 1H), 7.94 (d, J=7.9 Hz,1H), 7.86 (t, J=7.9 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H), 7.71 (s, 1H), 7.61(d, J=8.2 Hz, 1H), 4.71 (d, J=5.8 Hz, 2H), 3.29 (s, 3H), 2.01 (s, 3H);

APCI-MS m/z: 467.0 [MH⁺].

5-Methyl-N-{[5-(methylsulfonyl)-pyridin-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide(0.097 g, 0.21 mmol) was dissolved in DMF (2 ml) in a vial. To thismixture was added N-bromosuccinimide (0.055 g, 0.31 mmol), and the vialwas sealed and the mixture was heated at 50° C. with stirring for 1 h.The crude mixture was added dropwise to water (40 ml) under magneticstirring. The precipitate was isolated by filtration to give 0.105 g(92%) of6-bromo-5-methyl-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamideas a solid.

¹H NMR (400 MHz, DMSO-D₆) δ 9.80 (t, J=6.0 Hz, 1H), 8.99 (d, J=2.10 Hz,1H), 8.29 (dd, J=8.2 and 2.3 Hz, 1H), 8.00-7.94 (m, 2H), 7.88 (t, J=8.3Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 4.72 (d, J=5.7Hz, 2H), 3.30 (s, 3H), 2.15 (s, 3H);

APCI-MS m/z: 544.9 and 546.9 [MH⁺].

Starting Material SM4

[1-(4-Cyanophenyl)-1H-pyrazol-5-yl]boronic acid

4-(1H-Pyrazol-1-yl)benzonitrile (Eur. J. Org. Chem. 2004, 695-709) (1.5g, 8.87 mmol) in dry THF (50 ml) under argon was stirred at −78° C.whilst lithium diisopropylamide (1.8M solution in THF/hexane/ethylbenzene; 5.2 ml, 9.32 mmol) was added dropwise during 20 min. Stirringand cooling were continued for 1 h, triisopropyl borate (8 ml, 34.5mmol) was added dropwise during 30 min and then the temperature wasallowed to rise overnight to RT. The pH of the reaction mixture wasadjusted to 5 with 1M HCl and the mixture was then concentrated to aminimum volume and extracted with ethyl acetate (200 ml) and brine(3×100 ml). The organic phase was collected, dried (Na₂SO₄), filteredand evaporated to a brown solid (1.32 g) which was used in the next stepwithout further purification.

APCI-MS m/z: 214.1 [MH⁺].

Human Neutrophil Elastase Quenched-FRET Assay

The assay uses Human Neutrophil Elastase (HNE) purified from serum(Calbiochem art. 324681; Ref. Baugh, R. J. et al., 1976, Biochemistry.15, 836-841). HNE was stored in 50 mM sodium acetate (NaOAc), 200 mMsodium chloride (NaCl), pH 5.5 with added 30% glycerol at −20° C. Theprotease substrate used was Elastase Substrate V Fluorogenic,MeOSuc-AAPV-AMC (Calbiochem art. 324740; Ref. Castillo, M. J. et al.,1979, Anal. Biochem. 99, 53-64). The substrate was stored in dimethylsulphoxide (DMSO) at −20° C. The assay additions were as follows: Testcompounds and controls were added to black 96-well flat-bottom plates(Greiner 655076), 1 μL in 100% DMSO, followed by 30 μL HNE in assaybuffer with 0.01% Triton (trade mark) X-100 detergent. The assay bufferconstitution was: 100 mM Tris(hydroxymethyl)aminomethane (TRIS) (pH 7.5)and 500 mM NaCl. The enzyme and the compounds were incubated at roomtemperature for 15 minutes. Then 30 μl substrate in assay buffer wasadded. The assay was incubated for 30 minutes at room temperature. Theconcentrations of HNE enzyme and substrate during the incubation were1.7 nM and 100 μM, respectively. The assay was then stopped by adding 60μl stop solution (140 mM acetic acid, 200 mM sodium monochloroacetate,60 mM sodium acetate, pH 4.3). Fluorescence was measured on a Wallac1420 Victor 2 instrument at settings: Excitation 380 nm, Emission 460nm. IC₅₀ values were determined using Xlfit curve fitting using model205.

When tested in the above screen, the compounds of the Examples gave IC₅₀values for inhibition of human neutrophil elastase activity of less than30 μM (micromolar), indicating that the compounds of the invention areexpected to possess useful therapeutic properties. Specimen results areshown in the following Table:

Inhibition of Human Neutrophil Elastase IC₅₀ Compound (micromolar, μM)Example 1 0.00033 Example 2 0.00032 Example 12 0.0010 Example 16 0.00061

1. A compound of formula (I)

wherein R¹ represents hydrogen or C₁-C₆ alkyl; W represents a 5-memberedheterocyclic ring comprising at least one ring heteroatom selected fromnitrogen, oxygen and sulphur, wherein at least one of the ring carbonatoms may be optionally replaced by a carbonyl group; and wherein theheterocyclic ring is optionally substituted by at least one substituentselected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, OH, NO₂, C₁-C₃alkyl substituted by one or more F atoms, C₁-C₃ alkoxy substituted byone or more F atoms, NR¹⁰R¹¹, C≡CR¹⁵, CONR¹⁶R¹⁷, CHO, C₂-C₄ alkanoyl,S(O)_(x)R¹⁸ and OSO₂R¹⁹; R¹⁴ represents phenyl or a 6-memberedheteroaromatic ring comprising 1 to 3 ring nitrogen atoms; said ringbeing optionally substituted with at least one substituent selected fromhalogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, CN, OH, NO₂, C₁-C₃ alkyl substitutedby one or more F atoms, C₁-C₃ alkoxy substituted by one or more F atoms,NR¹²R¹³, C≡CR³⁰, CONR³¹R³², CHO, C₂-C₄ alkanoyl, S(O)_(p)R³³ andOSO₂R³⁴; R¹⁰, R¹¹, R¹² and R¹³ independently represent H, C₁-C₆ alkyl,formyl or C₂-C₆ alkanoyl; or the group —NR¹⁰R¹¹ or —NR¹²R¹³ togetherrepresents a 5 to 7 membered azacyclic ring optionally incorporating onefurther heteroatom selected from O, S and NR²⁶; R¹⁵ and R³⁰independently represent H, C₁-C₃ alkyl or Si(CH₃)₃; R¹⁸, R¹⁹, R³³ andR³⁴ independently represent H or C₁-C₃ alkyl; said alkyl beingoptionally substituted by one or more F atoms; R³ represents phenyl or afive- or six-membered heteroaromatic ring containing 1 to 3 heteroatomsindependently selected from O, S and N; said ring being optionallysubstituted with at least one substituent selected from halogen, C₁-C₆alkyl, cyano, C₁-C₆ alkoxy, nitro, methylcarbonyl, NR³⁵R³⁶, C₁-C₃ alkylsubstituted by one or more F atoms or C₁-C₃ alkoxy substituted by one ormore F atoms; R³⁵ and R³⁶ independently represent H or C₁-C₃ alkyl; saidalkyl being optionally further substituted by one or more F atoms; R⁴represents hydrogen or C₁-C₆ alkyl optionally substituted with at leastone substituent selected from fluoro, hydroxyl and C₁-C₆ alkoxy; Xrepresents a single bond, O, NR²⁴ or a group —C₁-C₆ alkylene-Y—, whereinY represents a single bond, oxygen atom, NR²⁴ or S(O)_(w); and saidalkylene being optionally further substituted by OH, halogen, CN,NR³⁷R³⁸, C₁-C₃ alkoxy, CONR³⁹R⁴⁰, CO₂R⁶⁶, SO₂R⁴¹ and SO₂NR⁴²R⁴³; or R⁴and X are joined together such that the group —NR⁴X together representsa 5 to 7 membered azacyclic ring optionally incorporating one furtherheteroatom selected from O, S and NR⁴⁴; said ring being optionallysubstituted by C₁-C₆ alkyl or NR⁴⁵R⁴⁶; said alkyl being optionallyfurther substituted by OH; either R⁵ represents a monocyclic ring systemselected from i) phenoxy, ii) phenyl, iii) a 5- or 6-memberedheteroaromatic ring comprising at least one ring heteroatom selectedfrom nitrogen, oxygen and sulphur, iv) a saturated or partiallyunsaturated C₃-C₆ cycloalkyl ring, and v) a saturated or partiallyunsaturated 4- to 7-membered heterocyclic ring comprising at least onering heteroatom selected from oxygen, S(O)_(r) and NR²⁰, wherein atleast one of the ring carbon atoms may be optionally replaced by acarbonyl group, or R⁵ represents a bicyclic ring system in which the tworings are independently selected from the monocyclic ring systemsdefined in ii), iii), iv) and v) above, wherein the two rings are eitherfused together, bonded directly to one another or are separated from oneanother by a linker group selected from oxygen, S(O)_(t) or C₁-C₆alkylene optionally comprising one or more internal or terminalheteroatoms selected from oxygen, sulphur and NR²⁷ and being optionallysubstituted by at least one substituent selected from hydroxyl, oxo andC₁-C₆ alkoxy, the monocyclic or bicyclic ring system being optionallysubstituted by at least one substituent selected from oxygen, CN, OH,C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen, NR⁴⁷R⁴⁸, NO₂, OSO₂R⁴⁹, CO₂R⁵⁰,C(═NH)NH₂, C(O)NR⁵¹R⁵², C(S)NR⁵³R⁵⁴, SC(═NH)NH₂, NR⁵⁵C(═NH)NH₂,S(O)_(v)R²¹, SO₂NR⁵⁶R⁵⁷, C₁-C₃ alkoxy substituted by one or more F atomsand C₁-C₃ alkyl substituted by SO₂R⁵⁸ or by one or more F atoms; saidC₁-C₆ alkyl being optionally further substituted with at least onesubstituent selected from cyano, hydroxyl, C₁-C₆ alkoxy, C₁-C₆ alkylthioand —C(O)NR²²R²³; or R⁵ may also represent H; R²⁰ represents hydrogen,C₁-C₆ alkyl, C₁-C₆ alkylcarbonyl or C₁-C₆ alkoxycarbonyl; R²¹ representshydrogen, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; said alkyl or cycloalkylgroup being optionally further substituted by one or more substituentsselected independently from OH, CN, C₁-C₃ alkoxy and CONR⁵⁹R⁶⁰; R³⁷ andR³⁸ independently represent H, C₁-C₆ alkyl, formyl or C₂-C₆ alkanoyl;R⁴⁷ and R⁴⁸ independently represent H, C₁-C₆ alkyl, formyl, C₂-C₆alkanoyl, S(O)_(q)R⁶¹ or SO₂NR⁶²R⁶³; said alkyl group being optionallyfurther substituted by halogen, CN, C₁-C₄ alkoxy or CONR⁶⁴R⁶⁵; R⁴¹ andR⁶¹ independently represent H, C₁-C₆ alkyl or C₃-C₆ cycloalkyl; p is 0,1 or 2; q is 0, 1 or 2; r is 0, 1 or 2; t is 0, 1 or 2; w is 0, 1 or 2;x is 0, 1 or 2; v is 0, 1 or 2; R¹⁶, R¹⁷, R²², R²³, R²⁴, R²⁶, R²⁷, R³¹,R³², R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁵, R⁴⁶, R⁴⁹, R⁵⁰, R⁵¹, R⁵², R⁵³, R⁵⁴,R⁵⁵, R⁵⁶, R⁵⁷, R⁵⁸, R⁵⁹, R⁶⁰, R⁶², R⁶³, R⁶⁴, R⁶⁵ and R⁶⁶ eachindependently represent hydrogen or C₁-C₆ alkyl; or a pharmaceuticallyacceptable salt thereof.
 2. The compound according to claim 1, whereinthe group R¹⁴ and the pyrazinone ring are bonded to the 5-membered ringW in a 1,2-relationship.
 3. The compound according to claim 1, whereinR³ represents a phenyl group substituted with one or two substituentsindependently selected from F, Cl, CN, NO₂ and CF₃.
 4. The compoundaccording to claim 1, wherein R¹⁴ represents a phenyl or pyridinyl groupoptionally substituted with one or two substituents independentlyselected from F, Cl, CN and CF₃.
 5. The compound according to claim 1,wherein R⁵ represents phenyl or pyridinyl substituted by —S(O)_(n)R²¹wherein v represents the integer
 2. 6. The compound according to claim1, wherein X represents unsubstituted C₁-C₂ alkylene.
 7. The compoundaccording to claim 1, wherein R⁵ represents H.
 8. The compound offormula (I) as defined in claim 1 selected from:6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylicacid methylamide;6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylicacid (5-methanesulfonyl-pyridin-2-ylmethyl)-amide;6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylicacid ethylamide;6-[1-(4-cyano-phenyl)-1H-1,2,3-triazol-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)-phenyl]-3,4-dihydro-pyrazine-2-carboxamide;tert-butyl2-[[6-[2-(4-cyanophenyl)pyrazol-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazine-2-carbonyl]amino]acetate;6-[3-(4-chloro-phenyl)-3H-[1,2,3]triazol-4-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylicacid methylamide;6-[2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-5-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,4-dihydro-pyrazine-2-carboxylicacid methylamide;6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-(2-methoxyethyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-(2-hydroxy-1,1-dimethylethyl)-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;6-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;6-[1-(6-cyanopyridin-3-yl)-1H-pyrazol-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;6-[1-(6-cyanopyridin-3-yl)-1H-pyrazol-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;6-[1-(5-cyanopyridin-2-yl)-1H-pyrazol-5-yl]-N,5-dimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;6-[1-(5-cyanopyridin-2-yl)-1H-pyrazol-5-yl]-N-cyclopropyl-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide;and2-[[6-[2-(4-cyanophenyl)pyrazol-3-yl]-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydro-pyrazine-2-carbonyl]amino]aceticacid; and pharmaceutically acceptable salts of any one thereof.
 9. Aprocess for the preparation of a compound of formula (I) or apharmaceutically acceptable salt thereof as defined in claim 1 whichcomprises, (a) reacting a compound of formula (II)

wherein L¹ represents a leaving group and R¹, R³, R¹⁴ and W are asdefined in claim 1, with a compound of formula

wherein X, R⁴ and R⁵ are as defined in claim 1; or (b) reacting acompound of formula (IV)

wherein Hal represents a halogen atom and X, R¹, R³, R⁴ and R⁵ are asdefined in claim 1, with a nucleophile R¹⁴—W-M wherein R¹⁴ and W are asdefined in claim 1 and M represents an organo-tin or organo boronic acidgroup; or (c) when W represents thiazolyl or oxazolyl, reacting acompound of formula (V)

wherein X, R¹, R³, R⁴, R⁵ and R¹⁴ are as defined in claim 1, withthiourea or formamide respectively; and optionally after (a), (b) or (c)carrying out one or more of the following: converting the compoundobtained to a further compound of the invention forming apharmaceutically acceptable salt of the compound.
 10. A pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof as claimed in claim 1 or claim 8 in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier. 11-14.(canceled)
 15. A method of treating, or reducing the risk of, a diseaseor condition in which inhibition of neutrophil elastase activity isbeneficial which comprises administering to a patient in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof as claimed in claim
 1. 16. Amethod of treating, or reducing the risk of, an inflammatory disease orcondition which comprises administering to a patient in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof as claimed in claim
 1. 17. Themethod according to claim 15 or claim 16, wherein the disease orcondition is adult respiratory distress syndrome (ARDS), cysticfibrosis, pulmonary emphysema, bronchitis including chronic bronchitis,bronchiectasis, chronic obstructive pulmonary disease (COPD), pulmonaryhypertension, asthma including refractive asthma, rhinitis, psoriasis,ischemia-reperfusion injury, rheumatoid arthritis, osteoarthritis,systemic inflammatory response syndrome (SIRS), chronic wound, cancer,atherosclerosis, peptic ulcers, Crohn'disease, ulcerative colitis orgastric mucosal injury.